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ID PMID Title PublicationDate abstract
8692761 [Prognosis of systemic diseases diagnosed in intensive care units]. 1996 May 25 OBJECTIVES: The aims of this study were to evaluate the prognosis of patients with systemic rheumatic disease diagnosed in medical intensive care unit (MICU) and to determine whether the outcome is different for patients with systemic rheumatic disease previously known hospitalized in MICU. METHODS: Retrospective evaluation, over a ten-year period, of 88 cases of systemic rheumatic disease selected in two groups: group I: diagnosed in MICU, group II: previously known and treated. RESULTS: Group I: 18 patients with necrotizing vasculitis (n = 6), extra-intestinal manifestations of inflammatory bowel disease (n = 4), systemic lupus erythematosus (n = 3), miscellaneous (n = 5). Group II: 70 patients with rheumatoid arthritis (n = 31), necrotizing vasculitis (n = 12), systemic lupus erythematosus (n = 12), polymyositis (n = 4), extra-intestinal manifestations of inflammatory bowel disease (n = 5), miscellaneous (n = 6). The main admission diagnoses were infectious diseases (p < 0.005) or iatrogenic complications in the group II (p < 0.01) and acute exacerbation of systemic rheumatic disease in the group I (p < 0.0001). Age; simplified acute physiologic score (SAPS); number of acute organ system failure; number of patients requiring mechanical ventilation, haemodialysis or right heart catheterization were not different between the two groups. The durations of mechanical ventilation and stay in the MICU were shorter in the group II (p < 0.005). MICU mortality rate was higher in the group II (p < 0.05), with a five years cumulative proportion of surviving statistically lower (p < 0.05). Mortality rate of the entire population (37.5%) was similar to that of a non-selected population with comparable SAPS. Multivariate analysis showed that SAPS, number of acute organ system failure and iatrogenic complications were the main prognostic factors (p = 0.05). CONCLUSIONS: The prognosis was better for patients with systemic rheumatic disease diagnosed in MICU. Infectious diseases were the main cause of death, probably in relation with immunosuppressive treatments.
8596155 Ultraviolet light and 8-methoxypsoralen inhibit expression of endothelial adhesion molecul 1995 Nov OBJECTIVE: Having previously found that treating small areas of synovitis within the knees of patients with rheumatoid arthritis (RA) with 8-methoxypsoralen (8-MOP) and laser-derived ultraviolet A (PUVA) resulted in decreases in adhesion molecule expression, we sought to determine the effect of PUVA on expression of vascular cellular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selection by human umbilical vein endothelial cells (HUVEC). METHODS: Expression of VCAM-1, ICAM-1, and E-selectin on the surface of HUVEC was measured using specific antibodies and flow cytometry or a fluorescence plate reader, following treatment of cells with 8-MOP and UVA, before and after tumor necrosis factor (TNF) stimulation. RESULTS: PUVA led to significant dose dependent decreases in the expression of VCAM-1 and E-selectin that had been induced with TNF before PUVA treatment. Pretreatment with PUVA was also able to prevent subsequent TNF induction of VCAM-1 expression. TNF-induced ICAM-1 expression was not decreased by PUVA, however, and pretreatment only partially decreased ICAM-1 expression. CONCLUSION: The in vivo effects of PUVA may be explained, in part, by down regulation of adhesion molecule expression. The relative resistance of ICAM-1 to PUVA suggests some specificity to the effect on adhesion molecule expression.
7543525 The antirheumatic drug disodium aurothiomalate inhibits CD4+ T cell recognition of peptide 1995 Aug 1 The mechanism of action of antirheumatic gold drugs, such as disodium aurothiomalate (Au(I)TM), has not been clearly identified. Gold drugs inhibit T cell activation induced by mitogen and anti-CD3 mAb in vitro at relatively high concentrations. However, since gold drugs fail to induce immunosuppression in vivo, the pharmacologic relevance of this finding is doubtful. In this study, we asked whether Au(I)TM interferes with processing and presentation of defined Ags to T cells. Using a panel of murine CD4+ T cell hybridomas, we found that low concentrations of Au(I)TM (< or = 10 microM) led to a markedly reduced IL-2 release of T cell hybridoma clones that recognized peptides containing two or more cysteine (Cys) residues, such as bovine insulin A1-14. Since disodium thiomalate alone had no effect, the inhibition was due to Au(I). IL-2 production induced by anti-CD3 mAb stimulation was not affected by the low concentration of Au(I)TM used. Au(I)TM had no effect on the presentation of peptides containing no or only one Cys residue(s). In contrast to the unmodified insulin peptide A1-14, Au(I) could not inhibit recognition of an insulin peptide in which Cys residues in positions 6 and 11 were replaced by serine. Most likely, the observed inhibition is mediated by formation of chelate complexes between Au(I) and two Cys thiol groups of the affected antigenic peptides. The peptide-specific inhibitory effect of Au(I) on Ag presentation described here might contribute to the therapeutic effect of Au(I) compounds in rheumatoid arthritis.
7718516 Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lympho 1995 Jan The CAMPATH-1 (CD52) antigen is a 21-28 kDa glycopeptide which is highly expressed on lymphocytes and macrophages and is coupled to the membrane by a glycosylphosphatidylinositol (GPI) anchoring structure. The function of this molecule is unknown. However, it is an extremely good target for complement-mediated attack and antibody-mediated cellular cytotoxicity. The humanized CAMPATH-1H antibody, which is directed against CD52, is very efficient at mediating lymphocyte depletion in vivo, and is currently being used in clinical trials for lymphoid malignancy and rheumatoid arthritis. It is therefore important to examine the functional effects of this antibody on different lymphocyte sub-populations. Because several other GPI-linked molecules expressed on the surface of T lymphocytes are capable of signal transduction resulting in cell proliferation, we have investigated whether the CAMPATH-1 antigen can also mediate these effects. In the presence of phorbol esters and cross-linking anti-Ig antibodies, mAbs specific for CD52 induced proliferation and lymphokine production in highly purified resting CD4+ and CD8+ T lymphocytes. The rat IgG2c YTH 361.10 anti-CD52 antibody, however, was able to activate resting CD4+ and CD8+ T cells directly without cross-linking or phorbol myristate acetate in the absence of Fc-bearing cells. Anti-CD52 antibodies also augmented the anti-CD3 mediated proliferative response of CD4+ and CD8+ T cells when the two antibodies were co-immobilized onto the same surface or cross-linked in solution by the same second antibody. Both CD4+ CD45RA and CD4+ CD45RO T cells were stimulated to proliferate by anti-CD52 antibodies in the presence of appropriate co-stimulatory factors. Anti-CD52 mAbs did not, however, synergize with anti-CD2 or CD28 mAb to induce CD4+ T cell proliferation. The activation of CD4+ T cells by anti-CD52 antibodies was inhibited by cyclosporin A, suggesting a role for the calcineurin-dependent signal transduction pathways. Although CD52 could transduce a signal in T cells, anti-CD52 antibodies did not inhibit antigen-specific or polyclonal T cell responses, suggesting this molecule does not play an essential co-stimulatory role in normal T cell activation.
7510346 Collagen cross-link metabolites in urine as markers of bone metastases in prostatic carcin 1994 Apr The efficacy of radionuclide bone scans in monitoring metastatic bone activity remains controversial. Objective measurement of bone tumor burden would be useful for the evaluation of new therapies for metastatic carcinoma of the prostate. The recent discovery of the urinary excretion of pyridinoline (cross-link of mature collagen found in cartilage and bone) and deoxypyridinoline (collagen cross-link specific to bone) measured by high pressure liquid chromatography has provided sensitive specific indexes of cartilage and bone breakdown in rheumatoid arthritis, osteoporosis and metabolic bone diseases. We compared the urinary excretion of deoxypyridinoline,pyridinoline and hydroxyproline relative to urinary creatinine (nmol./mmol.creatinine) in 27 patients with benign prostatic hyperplasia (patient age 70.0 +/- 8.5 years, standard deviation), 29 with clinically confined prostate cancer (age 70.2 +/- 9.7 years), and 26 with prostate cancer and bone metastases (age 71.1 +/- 7.7 years). No diurnal variation of deoxypyridinoline or pyridinoline urinary excretion was detected in 5 patients with metastases. Urinary excretion of pyridinoline and deoxypyridinoline was significantly greater in patients with metastatic carcinoma of the prostate compared with patients with either benign prostatic hyperplasia (Mann-Whitney-Wilcoxon rank sum analysis, p < 0.00004 and 0.002, respectively) or localized prostate cancer (Mann-Whitney-Wilcoxon, p < 0.00001 and 0.00005, respectively). Urinary hydroxyproline levels failed to separate the 3 groups. Pyridinoline and deoxypyridinoline excretion in prostate cancer patients with metastases directly correlated with bone scan Soloway scores (r = 0.55, p < 0.005 and r = 0.57, p < 0.004 respectively), whereas serum prostate specific antigen did not (r = 0.36, p = 0.08). Serial measurements of pyridinoline and deoxypyridinoline progressively increased in 3 patients with clinical progression documented by new metastatic lesions by bone scan. Measurement of pyridinoline and deoxypyridinoline excretion cannot diagnose metastatic disease. However, these markers should be evaluated further for quantitative assessment of bone metastases.
8082888 Characterization of the immunophenotype and functional properties of fibroblast-like synov 1994 Feb We characterized the immunophenotype as well as functional properties--phagocytosis, the uptake of acetylated LDL, and the expression of HLA class II antigens, adhesion molecules, and cytokine mRNA--of fibroblast-like synoviocytes from rheumatoid arthritis synovium. Skin fibroblasts (FB) and umbilical vein endothelial cells (HUVEC) were studied in parallel. Cytofluorometric immunophenotyping by use of 84 mAb and 2 lectins and immunofluorescence microscopy indicated a high degree of homology between the three cell types. Only staining with mAb to von Willebrand factor (vWF) and CD31 and the lectin UEA-I appeared specific to HUVEC, whereas the mAb 5B5 to prolyl 4-hydroxylase that has been reported to be specific to FB stained HUVEC as well as synoviocytes and FB. All of the cells phagocytosed fluorescent latex beads of 1.7 and 2.6 microns in size. The uptake of acetylated LDL could be shown by HUVEC and, surprisingly, by synoviocytes, but not by FB. The induction of HLA-DR, -DP, and -DQ by IFN-gamma on the three cell types showed a similar dose-dependence. The upregulation of ICAM-1 by IL-1 alpha, TNF-alpha, and IFN-gamma appeared similar, whereas the induction of VCAM-1 by IL-1 alpha, IL-4, TNF-alpha, and IFN-gamma showed differences between the three cell types. ELAM-1 was expressed only on HUVEC after treatment with IL-1 alpha and TNF-alpha. The capacity of the cells to produce cytokines was studied at the level of mRNA by reverse transcription and PCR. All three cell types expressed the mRNA of IL-1 alpha, IL-6, IL-8, GM-CSF, and TGF-beta 1 spontaneously or after LPS stimulation, but never TNF-alpha mRNA. Our results indicate a high degree of relationship between the three cell types. In contrast to HUVEC, none of the markers and functional properties investigated appear specific to FB. Therefore, the issue of the origin of fibroblast-like synoviocytes and the role of vascular endothelial cells in the inflamed synovium is discussed.
7920500 [Misoprostol in the prevention of gastric erosions caused by nonsteroidal anti-inflammator 1994 Feb A multicenter, double-blind, placebo-controlled study was carried out to determine whether the synthetic prostaglandin E1 analog misoprostol is effective in preventing gastric and duodenal lesions induced by nonsteroidal anti-inflammatory drugs. Two hundred fifty-six patients under nonsteroidal anti-inflammatory drug treatment (diclofenac, naproxen, piroxicam, ibuprofen, indomethacin, ketoprofen, or tiaprofenic acid) for osteoarthritis, rheumatoid arthritis, or other rheumatic diseases were included in the study. None of the patients had patent gastroduodenal damage at entry (0 to 3 mucosal erosions or subepithelial hemorrhages on endoscopy). Patients were randomly assigned to treatment with misoprostol 400 micrograms/d (M 400), misoprostol 800 micrograms/d (M 800) or a placebo. Results of the follow-up endoscopy on day 28 in the 186 evaluable patients showed that gastric erosions were significantly less common (p < or = 0.02) in the two misoprostol groups (5% and 2% in the M 400 and M 800 groups respectively) than in the placebo group (19%). Similar small numbers of patients in the three groups had gastric subepithelial hemorrhages or duodenal lesions. Three patients developed gastric ulcers in the placebo group, versus none in the misoprostol groups. Misoprostol therapy did not modify the efficacy of the nonsteroidal antiinflammatory agent on pain or other rheumatologic manifestations. Diarrhea occurred in 1%, 10%, and 5% of patients in the M 400, M 800, and placebo groups, respectively. In conclusion, misoprostol given in combination with a nonsteroidal anti-inflammatory agent for 28 days significantly reduced the incidence of gastric erosions in a random sample of patients with a variety of rheumatic diseases. The daily dosage associated with the best risk/benefit ratio may be 400 micrograms/day.
8172570 C1q inhibitor (chondroitin-4-sulfate proteoglycan): structure and function. 1993 Dec The serum C1q inhibitor (C1q INH) is a chondroitin 4-sulfate proteoglycan which is composed of several polyanionic components ranging in size from 21-750 kDa. Although the activity of C1q INH has been described in terms of its ability to precipitate C1q and inhibit its hemolytic activity, not much is known about either the mechanisms of its action or its role in health and disease. This report provides evidence that a 30 kDa core protein component of the proteoglycan macromolecule contains most of the C1q inhibitory activity. This inhibitory activity occurs as a result of C1q INH binding to the C1q "heads" (gC1q) as well as to the collagen "tail" (cC1q). What may be more significant in terms of perpetuation of inflammatory processes is the ability of C1q INH to moderately activate the classical pathway leading to C2 and C4 consumption. The binding of C1q INH to C1q is enhanced at low ionic strength, but significant binding does occur under physiologic conditions which makes it likely for the inhibitor to participate in inflammatory processes especially in microenvironments of high inhibitor concentration. Such elevated concentration does occur in patients with active rheumatoid arthritis and systemic lupus erythematosus either as a result of unregulated proteoglycan synthesis or disturbances in connective tissue metabolism. Another important function of serum C1q INH is its ability to prolong the clotting time of plasma and fibrinogen solutions containing or lacking CaCl2. This potent anticoagulant activity is again displayed by the 30 kDa putative protein core which specifically binds to both the E and D domains of fibrinogen. However, the epitope(s) on the 30 kDa which binds to C1q appears to be distinct from that which binds to fibrinogen. The known presence of proteoglycans on the basement membranes and other sites may explain at least in part the presence of fibrinogen in atheromatous lesions. Furthermore, by binding to fibrinogen, soluble C1q INH-and C1q-C1q INH complexes may limit fibrin gelation in inflammatory and tissue repair microenvironments.
7904547 Clinical pharmacokinetics of slow-acting antirheumatic drugs. 1993 Nov The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.
8260535 Interferon-gamma overcomes the glucocorticoid-mediated and the interleukin-4-mediated inhi 1993 Oct Interleukin-1 (IL-1) has been implicated in the tissue destruction of rheumatoid arthritis, a disease that is widely treated with glucocorticoids. In this study we investigated the effect of the T cell product interferon-gamma (IFN-gamma) on the glucocorticoid-mediated and on the IL-4-mediated inhibition of IL-1 beta mRNA and IL-1 beta protein synthesis in highly purified human monocytes. Both dexamethasone and IL-4 dose-dependently inhibited IL-1 beta mRNA and IL-1 beta protein synthesis after stimulation with LPS (300 ng/ml); maximal inhibition of 80-90% was achieved. IFN-gamma (1-100 U/ml) did not influence IL-1 beta mRNA and IL-1 beta protein levels in unstimulated cells, but potentiated the LPS-induced synthesis of IL-1 beta mRNA and IL-1 beta protein. After a preincubation time of 1 h, 100 U/ml of IFN-gamma increased the LPS-induced IL-1 beta production by about 20-40%. When human monocytes were preincubated for 1 h with IFN-gamma (100 U/ml) prior to the addition of dexamethasone (10(-6) M) and prior to the stimulation with LPS, the dexamethasone-mediated inhibition of IL-1 beta mRNA and IL-1 beta protein synthesis was totally neutralized by IFN-gamma. In addition, IFN-gamma totally overcame the negative effect of IL-4 (100 pM) on IL-1 beta protein synthesis. A preincubation period of at least 1 h with IFN-gamma was necessary for the neutralization of the dexamethasone effect. If IFN-gamma was given at the same time or after dexamethasone, only a weak effect was found.(ABSTRACT TRUNCATED AT 250 WORDS)
8340820 Diffusion of small solutes in cartilage as measured by nuclear magnetic resonance (NMR) sp 1993 Jul The ability of water and solutes to move through the cartilage matrix is important to the normal function of cartilage and is presumed to be altered in degenerative diseases of cartilage such as osteoarthritis and rheumatoid arthritis. Nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance imaging (MRI) techniques were used to measure a self diffusion coefficient (D) for small solutes in samples of explanted cartilage for diffusion times ranging from 13 ms to 2 s. With a diffusion time of 13 ms, the intratissue diffusivity of several small solutes (water, Na+, Li+, and CF3CO2-) was found consistently to be about 60% of the diffusivity of the same species in free solution. Equilibration of the samples at low pH (which titrates the charge groups so that the net matrix charge of -300 mM at pH 8 becomes approximately -50 mM at pH 2) did not affect the diffusivity of water or Na+. These data, and the similarity between the D in cartilage relative to free solution for water, anions, and cations, are consistent with the view that charge is not an important determinant of the intratissue diffusivity of small solutes in cartilage. With 35% compression, the diffusivity of water and Li+ dropped by 19 and 39%, respectively. In contrast, the diffusivity of water increased by 20% after treatment with trypsin (to remove the proteoglycans and noncollagenous proteins). These data and the lack of an effect of charge on diffusivity are consistent with D being dependent on the composition and density of the solid tissue matrix. A series of diffusion-weighted proton images demonstrated that D could be measured on a localized basis and that changes in D associated with an enzymatically depleted matrix could be clearly observed. Finally, evidence of restriction to diffusion within the tissue was found with studies in which D was measured as a function of diffusion time. The measured D for water in cartilage decreased with diffusion times ranging from 25 ms to 2 s, at which point the measured D was roughly 40% of the diffusivity in free solution. Although changes in matrix density by compression or digestion with trypsin led to a decrease or increase, respectively, in the measured D, the functional change in measured diffusivity with diffusion time remained essentially unchanged. In a different type of study, in which bulk transport could be observed over long periods of time, cartilage was submerged in 99% D2O and MRI studies were performed to demonstrate the bulk movement of water out of the cartilage matrix.(ABSTRACT TRUNCATED AT 400 WORDS)
8979155 Endogenous nitric oxide and prostaglandin E2 do not regulate the synthesis of each other i 1996 Dec Increased levels of nitric oxide (NO) and prostaglandins (PG) are present in the synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Interleukin-1 beta (IL-1) has been shown to induce the synthesis of both of these mediators. The present work was designed to study the interactions of NO and PGE2 synthesis induced by IL-1 in rat articular cartilage. Incubation of intact cartilage with IL-1 resulted in different dose response curves for NO and PGE2 synthesis. Two inhibitors of nitric oxide synthase N-monomethyl-L-arginine (L-NMMA) and L-N-iminoethylornithine, (L-NIO), abolished the IL-1-induced nitrite production but failed to have any influence on the PGE2 synthesis. Exogenous NO, produced by two chemically different NO-releasing compounds (SIN-1 and GEA 3175) had no effect on PGE2 synthesis in articular cartilage. Dexamethasone and ketoprofen inhibited IL-1 induced PGE2 production, while nitrite synthesis remained unaltered. Acetylsalicylic acid (ASA) reduced PGE2 synthesis and had a slight inhibitory action also on NO production. In conclusion, our results show, that IL-1 induces the synthesis of both PGE2 and NO in articular cartilage but these two inflammatory mediators are not mediating the synthesis of one another.
8670595 Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404. 1996 Jul The frequency of HLA-DRB1 alleles was determined in 68 Caucasoid patients with polymyalgia rheumatica (PMR) and 140 controls using polymerase chain reaction (PCR) sequence-specific oligonucleotide typing. In keeping with previous studies, an increased frequency of DRB1*04 was observed in patients [55.9% vs 35.0%, odds ratio (OR) 2.4, 95% confidence interval (CI) 1.3-4.4]. HLA-DRB1*0101 frequency was also increased in patients, although less confidence could be placed on this association (19.1% vs 14.3%, OR 1.4, 95% CI 0.6-3.3). HLA-DRB1*04 subtyping indicated that the frequencies of both DRB1*0401 (38.2% vs 22.1%, OR 2.2, 95% CI 1.0-4.3) and DRB1*0404 (16.2% vs 5.0%, OR 3.7, 95% CI 1.2-11.1) were specifically raised. An increased frequency of the RA shared epitope (QKRAA/QRRAA) was also observed in this group (75.0% vs 44.2%, OR 3.8, 95% CI 1.9-7.6). When the analysis was restricted to only DRB1*04-negative patients and controls, the frequencies of DRB1*0301, *11 and *08 were marginally raised. However, no obvious relationship appeared to exist between PMR susceptibility and DRB1 alleles carrying the DYF conserved epitope in the second hypervariable region. Autoantibodies to thyroid antigens were present in 23% of patients. An increased frequency of DRB1*0301 was observed in patients with thyroid microsomal antibodies compared to those without (54.5% vs 24.6%, OR 3.7, 95% CI 0.8-17.0). This increase was not observed in patients with thyroglobulin autoantibodies. These data indicate that both DRB1*0401 and *0404 are associated with PMR, and that this may extend to include DRB1*0101. The immunogenetic profile of susceptibility markers in this condition appears to be similar to that in rheumatoid arthritis.
8904250 [Research for basic and clinical aspects of Behcet's disease--recent advance and future--] 1996 Mar To elucidate the role played by HLA-B51 in the neutrophil hyperfunction of Behcet's disease, we determined the superoxide production by purified peripheral blood neutrophils from Behcet's disease patients, from HLA-B51 positive healthy individuals, and from HLA-B51 transgenic mice. As a result, a significant correlation between the neutrophil hyperfunction and the possession of HLA-B51 phenotype, regardless of the presence of the disease, was observed in humans. FMLP-stimulated neutrophils (without in vitro priming) from HLA-B51 transgenic mice, but not those from HLA-B35 transgenic mice or from nontransgenic mice, produced substantial amounts of superoxide. The HLA-B51 molecule itself may thus be responsible, at least in part, for neutrophil hyperfunction in Behcet's disease. CD4+ alphabeta T cells in this disease proliferated vigorously in response to specific peptide derived from human heat shock protein (HSP)-60; however, CD4+ alphabeta T cells from normal subjects or patients with rheumatoid arthritis did not. This peptide has the amino acid sequence 336-351 of human HSP60, which is similar, but not identical to specific peptide of mycobacterial HSP-65. To clarify whether the peptide stimulates patients' T cells as a polyclonal activator, a specific antigen or superantigen-like substance, we have also analyzed TCR usage of responsive T cells by means of TCR Vbeta subfamily-specific mAbs and PCR single strand conformation polymorphism-based technique. We found that T cells with specific TCR Vbeta subfamilies proliferated and increased in number in response to the peptide by an antigen-specific fashion. The result of recurrent exposure to the HSP may break the tolerance to self HSP, and provoke T cell responses to self and microbial HSP. Such T cells may produce Th1-like proinflammatory cytokines and lead to tissue injury possibly via delayed-type hypersensitivity reaction, macrophage activation, and activation and/or recruitment of neutrophils. Our data shed a new light on the autoimmune nature of Behcet's disease; a novel multistep molecular mimicry mechanism may induce and/or exacerbate Behcet's disease by bacterial antigens that activate T cells previously educated by self-peptide(s) of HSP. This would lead to positive selection of autoreactive T cells in this disease.
7623863 Cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risk 1995 Aug Cyclophosphamide (CP) is used to treat a wide range of neoplastic diseases as well as some non-malignant ones such as rheumatoid arthritis. It is also used as an immunosuppressive agent prior to organ transplantation. CP is, however, a known carcinogen in humans and produces secondary tumors. There is little absorption either orally or intravenously and 10% of the drug is excreted unchanged. CP is activated by hepatic mixed function oxidases and metabolites are delivered to neoplastic cells via the bloodstream. Phosphoramide mustard is thought to be the major anti-neoplastic metabolite of CP while acrolein, which is highly toxic and is produced in equimolar amounts, is thought to be responsible for most of the toxic side effects. DNA adducts have been formed after CP treatment in a variety of in vitro systems as well as in rats and mice using 3H-labeled CP. 32P-postlabeling techniques have also been used in mice. However, monitoring of adducts in humans has not yet been carried out. CP has also been shown to induce unscheduled DNA synthesis in a human cell line. CP has produced mutations in base-pair substituting strains of Salmonella tryphimurium in the presence of metabolic activation, but it has been shown to be negative in the E. coli chromotest. It has also been shown to be positive in Saccharomyces cerevisiae in D7 strain for many endpoints but negative in D62.M for aneuploidy/malsegregation. It has produced positive responses in Drosophila melanogaster for various endpoints and in Anopheles stephensi. In somatic cells, CP has been shown to produce gene mutations, chromosome aberrations, micronuclei and sister chromatid exchanges in a variety of cultured cells in the presence of metabolic activation as well as sister chromatid exchanges without metabolic activation. It has also produced chromosome damage and micronuclei in rats, mice and Chinese hamsters, and gene mutations in the mouse spot test and in the transgenic lacZ construct of Muta Mouse. Increases in chromosome damage and gene mutations have been found in the peripheral blood lymphocytes of nurses, pharmacists and female workers occupationally exposured to CP during its production or distribution. Chromosome aberrations, sister chromatid exchanges and gene mutations have been observed in somatic cells of patients treated therapeutically with CP. In general, there is a maximum dose and an optimum time for the detection of genetic effects because the toxicity associated with high doses of CP will affect cell division. In germ cells, CP has been shown to induce genetic damage in mice, rats and hamsters although the vast majority of such studies have used male mice.(ABSTRACT TRUNCATED AT 400 WORDS)
7706905 Cutaneous mast cell degranulation in rats receiving injections of recombinant human interl 1995 Apr Human recombinant interleukin-1 receptor antagonist (rhIL-1ra), a 17.2 kd protein is currently in clinical trials for the treatment of rheumatoid arthritis (RA). Skin reactions in some patients with RA prompted investigation of a possible pathogenesis involving nonimmunologically mediated mast cell degranulation. Rats injected intradermally with 20 microliters of rhIL-1ra (100 or 200 mg/ml) or the rhIL-1ra vehicle CSEP (10 mmol/L Na-citrate, 0.5 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1% polysorbate 80, 140 mmol/L NaCl, pH 6.5) had marked (15x or 10x, respectively) Evans blue dye permeability increases as compared with rats injected with phosphate-buffered saline solution (PBS) or bovine serum albumin (BSA). The permeability changes were reduced or eliminated by subcutaneous or local treatment with the antihistamine diphenhydramine. Histologic evaluation of skin sections from rats injected intradermally with CSEP or rhIL-1ra in CSEP revealed mast cell degranulation and edema, features not seen in sites injected with PBS or BSA in PBS. Components of the vehicle were investigated individually for their capacity to cause the reaction. Na-citrate (10 mmol/L) induced a greater increase in permeability than did EDTA (0.5 mmol/L) or polysorbate 80 (0.1%), and all produced reactions that were significantly greater than those occurring at PBS-injected sites. Evans blue dye permeability increases after subcutaneous injection of 1 ml of rhIL-1ra (100 mg/ml) in CSEP (with and without diphenhydramine) or rhIL-1ra in PBS were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)
7962020 Arthrodesis of the cervical spine for fractures and dislocations in children and adolescen 1994 Nov Forty-two patients who had had an arthrodesis for instability of the cervical spine resulting from trauma were followed clinically for a minimum of seven years (median, seventeen years and six months). The ages of the patients at the time of the injury ranged from one year and eleven months to fifteen years and eleven months. On the basis of a new post-traumatic neck score, which includes an assessment of pain, mobility, neurological status, and function, thirty-two patients (76 per cent) had an excellent result, six (14 per cent) had a good result, and four (10 per cent) had a fair result. No patient had a poor result. There was no notable deterioration of the clinical result with an increased duration of follow-up. Current radiographs of the cervical spine in flexion and extension were available for thirty-one (74 per cent) of the forty-two patients. There was no change in stability, deformity, or the fusion mass after healing or with an increased duration of follow-up, but there was a significant increase in osteoarthrotic changes in the unfused segments of the cervical spine after an increased duration of follow-up (p = 0.0001). Complications included spontaneous extension of the fusion mass in sixteen patients (38 per cent), mild pain or dysesthesias at the iliac-crest donor site in six patients (14 per cent), superficial infection at a bone-graft donor site in one patient (2 per cent), an incorrect level of arthrodesis in one patient (2 per cent). One patient had instability secondary to juvenile rheumatoid arthritis, which developed after treatment of the original injury, and she needed a reoperation. We concluded that spinal arthrodesis for fractures and dislocations of the cervical spine in children and adolescents can be accomplished safely, with an acceptable clinical outcome, a low rate of complications, and minimum morbidity after long-term follow-up. Pain, neurological status, and function do not change markedly, but mobility may decrease with an increased duration of follow-up. Our patients had a decrease in mobility, associated with an increase in osteoarthrotic changes, as seen on radiographs (p = 0.05).
8287559 A one-step sandwich enzyme immunoassay for tissue inhibitor of metalloproteinases-2 using 1993 Oct 29 A one-step sandwich enzyme immunoassay system was developed with a pair of monoclonal antibodies against two individual oligopeptides prepared from the amino acid sequence of the human tissue inhibitor of metalloproteinases-2 (TIMP-2). The assay system consisting of two simultaneous immunoreactions used a solid phase monoclonal antibody and a horse-radish peroxidase-labeled monoclonal antibody. The system detected a free form of TIMP-2 and that complexed with active forms of matrix metalloproteinases (MMPs) giving a different sensitivity for each MMP but not TIMP-2 complexed with the precursor of 72 kDa gelatinase/type IV collagenase (MMP-2). The sensitivity of the system was 1.6 microgram/l (16 pg/assay) and linearity was obtained between 6.3 and 50 micrograms/l (63-500 pg/assay). TIMP-2 levels in the sera of 20 patients with rheumatoid arthritis (68 +/- 25 micrograms/l, mean +/- S.D.) and 13 patients with hepatocellular carcinoma (76 +/- 46 micrograms/l) were significantly higher (P < 0.05) than those of 18 normal subjects (5.6 +/- 7.4 micrograms/l). In contrast, the levels in the sera of 10 patients with gastric cancer (45 +/- 18 micrograms/l) and 7 patients with cancer of the uterus (36 +/- 13 micrograms/l) were significantly lower (P < 0.05 or P < 0.01) than those of normal subjects. Immunoreactivity analyses suggested that the precursor of MMP-2 in normal sera exists in a complexed form with TIMP-2 by interacting with the C-terminal domain of TIMP-2.
7690874 Clinical significance of the antibody to the putative core protein of hepatitis C virus in 1993 Aug We evaluated the clinical significance of the antibody to hepatitis C core protein (anti-p22) analysing 147 sera from 99 patients; 45 of them had post-transfusion non A non B (NANB) hepatitis, 28 cryptogenic non A non B hepatitis, 12 chronic hepatitis B, 7 chronic hepatitis D, 6 other forms of liver disease (4 primary biliary cirrhosis, 2 autoimmune hepatitis) and 1 rheumatoid arthritis. All sera were tested by commercial 1st and 2nd-generation ELISAs and anti-p22 single antibody ELISA. We found a highly significant correspondence between anti-p22 and commercial assays (p = 0.0001). HCV-RNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR) in sera showing positive or negative concordant results and in all sera (24) that showed discordant results by anti-p22 and commercial ELISAs. HCV-RNA was found in 14 of 17 (82%) anti-p22 positive sera that were negative by commercial ELISAs, in 1 of 7 (14.3%) anti-p22 negative sera that were positive by commercial ELISAs (p = 0.001) and in all control sera from patients with positive concordant results. It was undetectable in 7 sera from patients with autoimmune diseases (negative by all ELISAs). We studied follow-up sera from 16 patients treated with interferon: 8 long-term responders (with persistently normal ALT levels for at least 24 months after discontinuation of therapy and histological remission) and 8 non-responders. Sera were also tested by a 4-antigen recombinant immunoblotting assay (RIBA II).(ABSTRACT TRUNCATED AT 250 WORDS)
7479938 Unimpaired autoreactive T-cell traffic within the central nervous system during tumor necr 1995 Nov 21 The critical role of tumor necrosis factor (TNF) as a mediator in autoimmune inflammatory processes is evident from in vivo studies with TNF-blocking agents. However, the mechanisms by which TNF, and possibly also its homologue lymphotoxin alpha, contributes to development of pathology in rheumatoid arthritis and Crohn disease and in animal models like experimental autoimmune encephalomyelitis is unclear. Possibilities include regulation of vascular adhesion molecules enabling leukocyte movement into tissues or direct cytokine-mediated effector functions such as mediation of tissue damage. Here we show that administration of a TNF receptor (55 kDa)-IgG fusion protein prevented clinical signs of actively induced experimental autoimmune encephalomyelitis. Significantly, the total number of CD4+ T lymphocytes isolated from the central nervous system of clinically healthy treated versus diseased control animals was comparable. By using a CD45 congenic model of passively transferred experimental autoimmune encephalomyelitis to enable tracking of myelin basic protein-specific effector T lymphocytes, prevention of clinical signs of disease was again demonstrated in treated animals but without quantitative or qualitative impediment to the movement of autoreactive T lymphocytes to and within the central nervous system. Thus, despite the uninterrupted movement of specific T lymphocytes into the target tissue, subsequent disease development was blocked. This provides compelling evidence for a direct effector role of TNF/lymphotoxin alpha in autoimmune tissue damage.