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ID PMID Title PublicationDate abstract
9383475 Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endotheli 1995 Oct BACKGROUND: Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a potent inducer of new blood vessel growth (angiogenesis) that contributes to the pathology of many angiogenesis-associated disease states such as psoriasis, rheumatoid arthritis and cancer. Few molecular entities capable of binding to VPF/VEGF with high affinity and specificity have been described to date. RESULTS: Nuclease-resistant 2'-amino-2'-deoxypyrimidine nucleotide RNA (2'-aminopyrimidine RNA) ligands that bind to VPF/VEGF with high affinity have been identified by iterative rounds of affinity-selection/amplification from two independent random libraries. The sequence information that confers high affinity binding to VPF/VEGF is contained in a contiguous stretch of 24 nucleotides, 5'-CCCUGAUGGUAGACGCCGGGGUG-3' (2'-aminopyrimidine nucleotides are designated with italic letters). Of the 14 ribopurines in this minimal ligand, 10 can be substituted with the corresponding 2'-O-methylpurine nucleotides without a reduction in binding affinity to VPF/VEGF. In fact, the 2'-O-methyl substitution at permissive positions leads to a approximately 17-fold improvement in the binding affinity to VPF/VEGF. The higher affinity results from the reduction in the dissociation rate constant of the 2'-O-methyl-substituted RNA ligand from the protein compared to the unsubstituted ligand. The 2'-O-methyl-substituted minimal ligand, which folds into a bulged hairpin motif, is also more thermally stable than the unsubstituted ligand. Nuclease resistance of the ligand is further improved by the 2'-O-methyl substitutions and the addition of short phosphorothioate caps to the 3'- and 5'-ends. CONCLUSIONS: We have used the SELEX (systematic evolution of ligands by exponential enrichment) process in conjunction with post-SELEX modifications to define a highly nuclease-resistant oligonucleotide that binds to VPF/VEGF with high affinity and specificity.
7539644 Further studies of the binding specificity of the leukocyte adhesion molecule, L-selectin, 1995 Feb This communication is concerned with the binding specificity of the leukocyte-adhesion molecule L-selectin (leukocyte homing receptor) towards structurally defined sulphated oligosaccharides of the blood group Le(a) and Le(x) series, and of the glycosaminoglycan series heparin, chondroitin sulphate and keratan sulphate. The recombinant soluble form of the rat L-selectin (L-selectin-IgG Fc chimera) investigated here was shown previously to bind to lipid-linked oligosaccharides 3-O, 4-O and 6-O sulphated at galactose, such as sulphatides and a mixture of 3-sulphated Le(a)/Le(x) type tetrasaccharides isolated from ovarian cystadenoma, as well as to the HNK-1 glycolipid with 3-O sulphated glucuronic acid. In the present study, the L-selectin investigated in both chromatogram binding and plastic microwell binding experiments using neoglycolipids was found to bind to the individual 3-sulphated Le(a) and Le(x) sequences (penta-, tetra- and trisaccharides), and with somewhat lower intensities to their non-fucosylated analogues. Glycosaminoglycan disaccharides of keratan sulphate, heparin and chondroitin sulphate types were also bound by L-selectin in one or both assay systems, leading to the conclusion that clustered glycosaminoglycan oligosaccharides with 6-O sulphation of N-acetylgalactosamine, N-acetylglucosamine or glucosamine, 4-O sulphation of N-acetylgalactosamine, 2-O sulphation of uronic acid, N-sulphation of glucosamine and, to a lesser extent, the non-sulphated uronic acid-containing disaccharides, can support L-selectin adhesion. As inflammatory chemokines (short-range stimulators of lymphocyte migration which trigger integrin activation) are known to bind to endothelial glycosaminoglycans, we propose that the binding of the lymphocyte membrane L-selectin to endothelial glycosaminoglycans may provide a link between the selectin-mediated and integrin-mediated adhesion systems in leukocyte extravasation cascades. The possibility is also raised that lymphocyte L-selectin interactions with glycosaminoglycans may contribute to pathologies of glycosaminoglycan-rich tissues, e.g. cartilage loss in rheumatoid arthritis and inflammatory lesions of the cornea.
7529605 The management of chronic graft-versus-host disease. 1994 Sep Chronic graft-versus-host disease (GVHD) is a major cause of late morbidity and mortality following allogeneic marrow transplantation. The pathogenesis and clinical features of chronic GVHD resemble those of several autoimmune diseases including progressive systemic sclerosis, systemic lupus erythematous, lichen planus, Sjögren's syndrome, rheumatoid arthritis, and primary biliary cirrhosis. Chronic GVHD retards the tempo of immune reconstitution following allogeneic transplantation and is a major risk factor for late infections. Although in vivo immunosuppression and in vitro depletion of T-cells can reduce the incidence of acute GVHD, improved long-term survival free of chronic GVHD has not been observed. Early treatment of multiorgan extensive chronic GVHD with an alternating-day regimen of cyclosporine and prednisone has led to improved disability-free survival. Functional performance of the long-term survivors receiving combination immunosuppressive therapy remained near normal and the incidence of disabling scleroderma has decreased from over 50% to 6%. However, infections remain a frequent cause of morbidity especially in high-risk patients with advanced age, HLA-nonidentical marrow grafts, progressive onset of chronic GVHD and continued thrombocytopenia.
7517872 CD57+ T lymphocytes are derived from CD57- precursors by differentiation occurring in late 1994 Jul CD3+ T cells expressing the 110-kDa CD57 antigen are found in survivors of renal, cardiac and bone marrow transplants, in patients with acquired immune deficiency syndrome and in patients with rheumatoid arthritis. They are also present in normal individuals and expand upon ageing. They do not grow in culture and their role in the immune response is poorly understood. The expression of the various isoforms of the leukocyte common antigen (CD45) identifies a spectrum of differentiation in CD4+ and CD8+ T cells ranging from naive (CD45RA+CD45RBbrightCD45RO-) through early primed cells (CD45RA-RBbrightROdull) to highly differentiated memory cells which are CD45RA-RBdullRObright. CD45 isoforms expressed by CD57+ T cells showed distinct differences between CD4+ and CD8+ populations, but in each case indicated an advanced state of differentiation. The expression of T cell receptor V beta families was highly variable between individuals, but both CD57+ and CD57- cells show a full range of the specificities tested. V beta expression was more closely related within either the CD4+ or the CD8+ subsets, irrespective of CD57 expression, than between these subsets, suggesting a relationship between CD57+ and CD57- cells within the same T cell pool. This possibility was supported by experiments showing that CD3+CD57+ lymphocytes were similar to CD3+CD57- T cells in terms of the production of basic T cell cytokines [interleukin (IL)-2, IL-4, and interferon-gamma]. Furthermore, in vitro stimulation of CD3+CD57- T cells in secondary mixed leukocyte reaction or by co-culture with IL-2 and IL-4 induced the appearance of CD3+CD57+ cells with phenotypic and functional similarities to in vivo CD3+CD57+ cells. These data strongly suggest that the expression of CD57 is a differentiation event which occurs on CD57- T cells late in the immune response.
7506665 Three novel synthetic retinoids, Re 80, Am 580 and Am 80, all exhibit anti-angiogenic acti 1993 Nov 2 In a previous study, we demonstrated that retinoic acid or a synthetic retinoid, Ch 55 ((E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid), significantly affects in vivo angiogenesis, on the basis of our working hypothesis that a cell differentiation modulator could also exhibit anti-angiogenic activity. In the present study, three novel synthetic retinoids, Re 80 (4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl- 2- naphthalenyl)-1-propenyl]benzoic acid), Am 580 (4-[(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid) and Am 80 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl] benzoic acid), whose cell differentiation-modulating effects are roughly comparable to or more potent than that of Ch 55, which was the most effective angiostatic retinoid identified previously, were examined. Their anti-angiogenic effects were tested in an in vivo assay system involving chorioallantoic membranes of growing chick embryos. They were all found to exert dose-dependent anti-angiogenic effects in the picomolar range. Their rank order for inhibitory potency was Re 80 > Am 580 > Am 80, the ID50 values being 6.3, 23 and 28 pmol/egg, respectively. These results indicate that treatment involving these three novel synthetic retinoids might have potential therapeutic efficacy in various angiogenesis-dependent disorders, including solid tumors, psoriasis, rheumatoid arthritis and diabetic retinopathy.
8170560 Environmental antecedents of young-onset Parkinson's disease. 1993 Jun We conducted an exploratory study of young-onset Parkinson's disease (YOPD) to examine occupational and environmental factors associated with disease risk. This case-control study included 63 YOPD patients (diagnosis on or before age 50); controls (n = 68) were diagnosed with rheumatoid arthritis. Crude odds ratios (ORs) were computed to identify exposure variables for logistic regression analyses. After controlling for the variables of race, educational level, sex, age, age at diagnosis, and family history of Parkinson's disease (PD), PD was positively associated with insecticide exposure (OR = 5.75, p < 0.001), past residency in a fumigated house (OR = 5.25, p = 0.046), herbicide exposure (OR = 3.22, p = 0.033), rural residency at time of diagnosis (OR = 2.72, p = 0.027), and nuts and seed eating 10 years before diagnosis (OR = 1.49, p = 0.021). PD was inversely associated with cigarette smoking at 5 years (OR = 0.50, p = 0.027), 10 years (OR = 0.43, p = 0.012), and 15 years (OR = 0.37, p = 0.005) before diagnosis, farm residency (OR = 0.38, p = 0.018), and exposure to dimethyl sulfoxide (OR = 0.10, p < 0.001). These findings are consistent with hypotheses linking PD to exposure to pesticide agents.
8458370 T and B cell immune response to a 55-kDa endothelial cell-derived antigen in severe asthma 1993 Apr Current concepts on the pathogenesis of chronic asthma emphasize the role of several inflammatory cell populations and their respective mediators that interact in a complex network. However, beside inflammatory cells, lymphocytes are also present in asthmatic airways. Although little is known about their involvement in asthma, it has been suggested that lymphocytes may participate in the development of chronic inflammation either through lymphokine secretion or through antibody production. In this study, we describe circulating IgG autoantibodies, directed against a common 55-kDa antigen shared by platelets and cultured endothelial cells, and found in 34 out of 97 asthmatic patients. Among epidemiological, clinical and biological characteristics of these asthmatic patients, the anti-55-kDa antigen antibodies are mainly restricted to patients with negative cutaneous prick tests (p = 0.0014), and corticosteroid-dependent asthma (p = 0.0036). These antibodies were also detected in a few patients with autoimmune disorders like systemic lupus erythematosus (3/30) or rheumatoid arthritis (2/36). Both platelet and endothelial cell antigens were cross-reactive, had an isoelectric point between 8.0 and 9.0, were insensitive to reducing agents such as 2-mercaptoethanol, and were not present on either platelet or endothelial cell surface, as determined by immunostaining assay. [3H]Thymidine incorporation assay with peripheral blood mononuclear cells from patients in the presence or in the absence of 55-kDa antigen, purified from nitrocellulose sheets demonstrated a specific incorporation in 6 out of 13 patients with circulating anti-55-kDa antigen antibodies, with index values ranging from 12 to 3. Such a T cell reactivity has also been observed in 3 out to 17 patients without detectable serum anti-55-kDa antigen antibodies. Moreover, a significant correlation was found between index values of antigen-specific T cell reactivity and the forced expiratory volume in one second (r = 0.544, p = 0.003). Our data indicate that the detection of such antibodies allows to distinguish a subgroup of asthmatics in terms of severity and to suggest a relationship between clinical severity and T and B cell autoreactivity to the 55-kDa platelet/endothelial cell antigen.
8094974 P-glycoprotein expression in normal and reactive bone marrows. 1993 Mar The expression of mdr1 gene product P-glycoprotein (P-gp) was investigated in 53 normal and reactive bone marrows by means of immunocytochemistry, using the monoclonal antibody (mAb) C219 and the alkaline phosphatase anti-alkaline phosphatase method. In a limited number of patients, data were confirmed by using the mAb MRK16 or a polymerase chain reaction assay for mdr1 gene expression. There was no history of prior chemotherapy or any malignancy in this group. Bone marrow aspirates were obtained as part of a routine diagnostic programme in bone marrow donors or in patients presenting with a variety of diagnoses such as unexplained gammopathy, fever, anaemia, other changes in peripheral blood smear, rheumatoid arthritis, vasculitis, or urticaria pigmentosa. Morphologically the bone marrow was normal in 23 patients, a megaloblastic erythropoiesis was seen in two patients and unspecific changes were seen in 28 patients. Twenty-seven of 53 samples were found to be positive for P-gp expression with the percentage of positive cells ranging from 2%-80% (mean = 24%). With a cutoff point of 10%, five of 23 normal (22%) and 13 of 28 reactive bone marrows (46%) were considered positive for P-gp expression. There was no obvious correlation between diagnosis or age and P-gp expression. Additional staining for the early surface marker CD-34 was performed in 12 samples, with none of them revealing more than 1% positivity. Since P-gp expression has so far been described only in CD-34 positive bone marrow cells, data suggest that P-gp expression may be reinduced in CD-34 negative cells under conditions which remain to be determined.
1596015 Neutrophilic alveolitis in idiopathic pulmonary fibrosis. The role of interleukin-8. 1992 Jun Idiopathic pulmonary fibrosis is an immunologically mediated pulmonary disorder in which activated alveolar macrophages (AM) and neutrophils play cardinal roles in the pathogenesis of the inflammatory lung lesion. The factors responsible for the induction and perpetuation of the neutrophilic alveolitis are not known. Recently, a novel cytokine (Interleukin-8) was described that is released by activated mononuclear phagocytes and a variety of other cell types, and it exhibits potent chemotactic activity for polymorphonuclear leukocytes (PMN). Increased expression of IL-8 has been described in other inflammatory disorders characterized by neutrophilic infiltration, including psoriasis, rheumatoid arthritis, and the sepsis syndrome, but no studies have assessed this cytokine in the context of interstitial pulmonary disorders. We have previously shown that normal human AM release IL-8 upon appropriate stimulation, but data assessing the expression of IL-8 by human AM in specific pulmonary disease states are lacking. In this study, we examined the expression of steady-state mRNA for IL-8 by human alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis and from healthy volunteers. Because it is known that adherence to plastic culture plates may up-regulate gene expression for IL-8 in the absence of additional stimulation, we extracted mRNA immediately from the cell pellet obtained by BAL rather than using cultured alveolar macrophage monolayers. Northern blot analysis was performed to determine IL-8 mRNA expression. We found that BAL cells from patients with IPF constitutively expressed mRNA for IL-8, and the amount of IL-8 mRNA (as assessed by laser densitometry) correlated with the percent of neutrophils on BAL.(ABSTRACT TRUNCATED AT 250 WORDS)
8941674 IL-4 upregulates tenascin synthesis in scleroderma and healthy skin fibroblasts. 1996 Dec Tenascin (TN), a large extracellular matrix glycoprotein, is transiently expressed during embryonic development, but is absent from most normal adult tissues. TN is reexpressed, however, in healing wounds, in the stroma of some tumors, and in fibrotic diseases such as systemic sclerosis (SSc) and rheumatoid arthritis. To clarify the mechanisms regulating TN expression, we studied the effects of selected cytokines (PDGF, bFGF, TGF-beta, IL-1, IL-4, IL-6, IFN-gamma, and TNF-alpha) found in fibrotic tissue on TN expression by dermal fibroblasts. IL-4 strongly induced TN protein levels (up to 10-fold over the basal level), whereas PDGF and bFGF were less potent inducers of TN than IL-4. All other cytokines tested, including TGF-alpha1, did not stimulate TN synthesis. IL-4 also increased TN mRNA expression, and this effect was blocked by actinomycin D. Cycloheximide increased basal TN mRNA expression and induced TN mRNA in IL-4-treated fibroblasts, suggesting that repressor protein(s) may regulate transcription of the TN gene. Although no differences in constitutive TN expression or effects of cytokines on TN expression were observed between SSc and healthy fibroblasts, these data are consistent with the observations that high levels of both IL-4 and TN are present in the affected skin of patients with SSc. These results suggest that the high level of TN found in the affected tissue of patients with SSc results from the high level of IL-4 present.
9004439 Application of murine T-T hybridoma cells to in vitro potency assay of human synthetic pep 1996 Oct Recently, it has been shown that the immunization of mice with an 18 amino acid synthetic peptide corresponding to the third hypervariable region of MHC class II beta chain can induce a specific antibody response against MHC class II molecules, and can be utilized in the prevention and treatment of experimental allergic encephalomyelitis (EAE) [Proc. Natl. Acad. Sci. 1994, 91, 8005-8009]. Based on this finding, a chemically-modified synthetic peptide with the amino acid sequence corresponding to residues of beta 57-76 from human HLA-DR4Dw4 (DR4/1 peptide) is being clinically investigated for the treatment of rheumatoid arthritis in human. The present study describes the development of a novel in vitro potency assay for human HLA-DR4/1 peptide using cloned murine T-T hybridoma cells. Several mouse strains were immunized with the DR4/1 peptide and their lymph node T cell proliferation was measured in the presence of syngeneic APCs and the DR4/1 peptide. T cells isolated from the peptide primed-B10. PL mouse strain, which showed the highest recall response in this assay, were fused with BW5147 lymphoma cells to generate DR4/1 peptide-specific T-T hybridoma clones. Cloned hybridoma cells were characterized for peptide specificity and MHC class II restriction, and used to monitor the biological activity of various DR4/1 peptide preparations. The potency of peptide batches were assessed by measuring the IL-2 secretion of cloned T-T hybridoma cells upon TCR engagement in an antigen-specific manner. The quantitative detection of IL-2 was performed by measuring [3H]thymidine incorporation of HT-2 cells or directly by ELISA. These results demonstrate that peptide-specific murine T-T hybridoma clones can be successfully utilized to monitor biological activity of synthetic peptides by measuring T cell-mediated immunological responses. Development of such in vitro potency assay for synthetic peptides may have broad applications for vaccines related to immunological disorders.
8705689 [Serum CA 19-9 levels in rheumatic diseases with interstitial pneumonia]. 1996 Apr Serum CA 19-9 (2-3 sialyl Le(a)) is a marker of malignant disorder such as pancreas or gall bladder cancers. It has been reported that sera from patients with interstitial pneumonia show elevated level of CA 19-9. To investigate the relationship between the elevation of serum CA 19-9 (sCA 19-9) and the presence of pulmonary fibrosis, we examined the level of sCA 19-9 in sera from patients with rheumatic diseases with or without interstitial pneumonia (IP). The sCA 19-9 level was determined by enzyme-linked immunosorbent assay (ELISA). Fourteen sera of 129 (10.9%) patients with rheumatic diseases without malignant disorders were positive for sCA 19-9 when normal range was determined as less than 100 U/ml (mean +/- 5 SD), and 26.7% of sera from poly/dermatomyositis (PM/DM) and 11.8% of systemic sclerosis (PSS) were positive for CA 19-9. Whereas only 8.0% of rheumatoid arthritis (RA) was positive. Twelve (28.6%) of 42 rheumatic patients with IP showed positive levels for sCA 19-9 (mean 142.5 +/- 363.0 U/ml), whereas only two (2.3%) of 87 without IP were positive (mean 33.9 +/- 65.8 U/ml; p < 0.05). The correlation between the level of sCA 19-9 and pulmonary diffusing capacity (%DLCO) revealed an inverse correlation in 32 rheumatic patients with IP (r = -0.43, p < 0.05). Furthermore, the elevated sCA 19-9 levels decreased after treatment with corticosteroid and/or cyclophosphamide or cyclosporin A. Therefore, elevation of the level of sCA 19-9 seems to be involved in the pathogenesis of IP and sCA 19-9 will be a useful parameter for IP. It has been reported that the CA 19-9 is produced from the bronchial glands and suggested that during chronic fibrotic process of the lung, the metaplastic change of the bronchial glandular cells occur and the cells produce CA 19-9.
8690925 Increased frequency of abnormal gamma delta T cells in blood of patients with inflammatory 1996 Mar 15 We have previously reported a preferential usage of V delta 1/V gamma 8 on TCR-gamma-delta-bearing intraepithelial lymphocytes of the normal human intestine as well as in the inflamed synovial tissue of patients with rheumatoid arthritis. The aim of the present study was to analyze V gene segment usage by gamma delta T cells of the intestine and peripheral blood (PB) from patients with inflammatory bowel disease. Freshly isolated lymphocytes were analyzed by flow cytometry using a panel of V gene subset-specific mAbs. The relative proportion of PB TCR-gamma delta+ cells was increased in patients with Crohn's disease as compared with controls. Interestingly, an increased proportion of PB gamma delta T cells of patients with ulcerative colitis or CrD expressed V delta and V gamma genes typically used by intraepithelial lymphocytes. Thus, increased proportions of V delta 1+ and V gamma 8+ cells were found in the PB of both patient groups. The majority of TCR-gamma delta+ intraepithelial lymphocytes (IEL) in inflamed and noninflamed intestine expressed V delta 1/V gamma 8, and a substantial proportion of V gamma(2,3,4)+ cells were found. These observations suggest a disease-associated appearance of "gut-like" gamma delta T cells in the periphery. Moreover, two patients had a large proportion of gamma delta T cells in their PB of which the majority expressed two distinct V gamma proteins. Both of these patients had a short duration of disease (1 and 10 mo, respectively) and the relative proportion of gamma delta T cells decreased in concert with stabilization of disease. Interestingly, one of the patients had a clonal expansion of a V gamma dual-expressing gamma delta T cell in the PB.
9044307 Lipoxidation products as biomarkers of oxidative damage to proteins during lipid peroxidat 1996 Oxidative stress is implicated in the pathogenesis of numerous disease processes including diabetes mellitus, atherosclerosis, ischaemia reperfusion injury and rheumatoid arthritis. Chemical modification of amino acids in protein during lipid peroxidation results in the formation of lipoxidation products which may serve as indicators of oxidative stress in vivo. The focus of the studies described here was initially to identify chemical modifications of protein derived exclusively from lipids in order to assess the role of lipid peroxidative damage in the pathogenesis of disease. Malondialdehye (MDA) and 4-hydroxynonenal (HNE) are well characterized oxidation products of polyunsaturated fatty acids on low-density lipoprotein (LDL) and adducts of these compounds have been detected by immunological means in atherosclerotic plaque. Thus, we first developed gas chromatography-mass spectrometry assays for the Schiff base adduct of MDA to lysine, the lysine-MDA-lysine diimine cross-link and the Michael addition product of HNE to lysine. Using these assays, we showed that the concentrations of all three compounds increased significantly in LDL during metal-catalysed oxidation in vitro. The concentration of the advanced glycation end-product N epsilon-(carboxymethyl)lysine (CML) also increased during LDL oxidation, while that of its putative carbohydrate precursor the Amadori compound N epsilon-(1-deoxyfructose-1-yl)lysine did not change, demonstrating that CML is a marker of both glycoxidation and lipoxidation reactions. These results suggest that MDA and HNE adducts to lysine residues should serve as biomarkers of lipid modification resulting from lipid peroxidation reactions, while CML may serve as a biomarker of general oxidative stress resulting from both carbohydrate and lipid oxidation reactions.
8676117 Indications for total hip and total knee arthroplasties. Results of orthopaedic surveys. 1996 Jan A lack of consensus regarding the indications for total hip arthroplasty (THA) and total knee arthroplasty (TKA) has been cited as one reason for the variations in the rates of THA and TKA across the United States. The purposes of this study were to survey orthopaedists in a specific geographic area (New York City) regarding the candidacy of patients with osteoarthritis for THA or TKA and to compare indications for THA between orthopaedists at two academic medical centers, The Hospital for Special Surgery in the United States and McGill University in Canada. Orthopaedists were sent mail surveys asking about indications, factors affecting outcomes, and factors that might modify decisions for surgery. Approximately 45% of orthopaedists who performed THA and TKA in New York City in 1992 completed the surveys. Although there were wide variations among surgeons, most surgeons required at least severe pain daily, rest pain several days per week, transfer pain either several days per week (THA) or daily (TKA), and destruction of most of the joint space on radiograph. Younger age, comorbidity, technical difficulties, and lack of motivation modified the decision against surgery, whereas the desire to be independent and return to work swayed the decision for surgery. Most surgeons rated that patients with severe pain, osteoarthritis, or rheumatoid arthritis would have a high likelihood of an excellent outcome, whereas those with comorbidity and certain technical factors would have only a moderate likelihood of an excellent outcome. In the U.S.-Canadian survey of THA, in which more than 90% of surgeons responded, Canadian surgeons tended to require more frequent pain and use of assistive devices for walking. Although there was a majority of opinion for several indications, there was no clear consensus among surgeons regarding the indications for THA and TKA. Possible explanations for this are that isolated indications are not as important as integrating and weighing several indications and that the patient's desire to proceed with THA or TKA is an important driving force in the decision to operate.
7621584 IL-13 results in differential regulation of the complement proteins C3 and factor B in tum 1995 Jul IL-13, like IL-4, a product of activated T cells, has multiple biological actions, primarily on B cells and monocytes. The purpose of the present study was to compare the effects of IL-13 with those of IL-4 on the synthesis of complement proteins in fibroblasts. Dermal fibroblasts were developed from skin biopsies. Confluent monolayers were stimulated with the relevant cytokine or combinations of cytokines and biosynthetically labelled with 35S-methionine. The specific proteins were analysed using immunoprecipitation and SDS-PAGE. Addition of IL-13 to fibroblast cultures treated with TNF-alpha resulted in a dose-dependent increase in C3 protein biosynthesis and a concomitant down-regulation of factor B protein biosynthesis. In TNF-stimulated fibroblasts, the addition of IL-13, 100 ng/ml, induced a 2.45-fold increase in the synthesis of C3, while in the same cells under identical conditions the synthesis of factor B was only 42% of the level without IL-13. Similar effects of IL-13 were noted on IL-1-treated fibroblasts. These effects were specific for C3 and factor B, and no alteration of the constitutive or TNF-induced synthesis of C1s or C1 inhibitor proteins was observed. IL-13 altered the synthesis of C3 and factor B proteins also in fibroblasts stimulated with interferon-gamma (IFN-gamma) in addition to TNF, in the same direction as it did in cells stimulated with TNF alone. IL-13 has similar effects to those of IL-4 on the synthesis of C and factor B in TNF- and IL-1-stimulated fibroblasts. The observed effects of IL-13 are IL-4-independent, as anti-IL-4 antibody abrogates IL-4-induced effects, but has no effect on IL-13-induced responses. This interaction between different cytokines on the synthesis of proinflammatory and immunoregulatory proteins may have significance, particularly at local sites of inflammation, and may affect the synthesis of complement proteins in inflamed joint as in rheumatoid arthritis.
7586781 D-penicillamine-induced autoantibodies in a mouse model. 1995 Jul OBJECTIVE: We have previously shown that the administration of D-penicillamine (D-PEN) to patients with rheumatoid arthritis induces circulating insulin autoantibodies (INSAAB). In order to gain further insight into such immune responses, we measured a battery of circulating autoantibodies in 4 strains of mice receiving D-PEN: C57BL/KsJ, BALB/c, C3H/HeJ, and C57BL/6. These rodents groups differ in their degree of susceptibility to streptozotocin (STZ)-induced immune diabetes (SIMD), which is high in the first 2 strains, and mild and nil in the third and fourth, respectively. METHODS: Randomly assigned animals from each group were given a weekly subcutaneous (SC) injection of either D-PEN 1 mg, D-PEN 3 mg, or solvent (PBS) for a period of 4 weeks. Serum levels of antibodies to insulin, single stranded DNA (ssDNA), thyroglobulin, and cardiolipin were measured weekly. RESULTS: Only the C57BL/KsJ and C3H/HeJ mice reacted to D-PEN administration. When compared to the pre-treated and solvent-treated mice, D-PEN 1 mg, and to a lesser degree D-PEN 3 mg, induced elevation of antibodies to insulin and to ssDNA in C57/KsJ mice (p < 0.001), while only ssDNA antibodies were detected in the C3H/HeJ mice (p < 0.0001 for D-PEN 1 mg; p < 0.05 for D-PEN 3 mg). D-PEN had no effect on the level of antibodies to cardiolipin or to thyroglobulin in any of the mice. CONCLUSIONS: This study showed that D-PEN induces an antigen(s)-specific humoral response only in mice already inherently prone to autoimmunity. This model suggests that the activation of autoimmunity by environmental factors is probably facilitated by genetic background, and might partly explain the diversity of autoimmune manifestations in D-PEN-treated patients.
7562759 Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in 1995 Jul OBJECTIVE: Assessment of the inter and intraobserver variability of the modified Rodnan (m-Rodnan) total skin thickness score by clinical palpation [a commonly used outcome measure in trials of systemic sclerosis (SSc)]. METHODS: Skin thickness was assessed by clinical palpation of 17 body areas on 0 to 3 scale (normal, mild, moderate, severe). The m-Rodnan total skin thickness score was derived by summation of the scores from all 17 body areas. Using the m-Rodnan, 6-7 investigators assessed skin thickness in 5-6 patients with SSc (22 patients and 23 examiners total) at each of 4 sessions for the determination of interobserver variability (accuracy). In addition 21 of the investigators then assessed m-Rodnan in 2-3 patients each (60 patients total) 3 times over a 2-8 week period to quantitate intraobserver variability (reliability). RESULTS: Interobserver and intraobserver mean +/- within patient standard deviations (SD) for the m-Rodnan were found to be 17.7 +/- 4.6 and 20.7 +/- 2.45, respectively. CONCLUSION: The m-Rodnan total skin thickness score is at least as reliable for measuring skin thickness in SSc as are the ARA and Ritchie joint tenderness counts for assessing joint disease in rheumatoid arthritis. These data are useful for the determination of sample size and for the definitions of clinically meaningful response. Assessment of skin score is sufficiently reproducible to include as a measure of disease outcome, especially if patients are serially evaluated by the same investigator.
8519517 Aortic root replacement with a pulmonary autograft. 1995 A series of 42 consecutive patients with exclusively aortic root replacement using the pulmonary autograft is presented. The mean age at operation was 19.3 years (range 0.3-41.4). Two patients died in hospital (4.8%; 70% CL: 0.0-8.2). This mortality was not related to the autograft procedure. The mean follow-up time was 30 months (range 3-70; SD: 20). Late mortality consisted of two patients; in one of these severe autograft failure occurred due to chronic juvenile rheumatoid arthritis. The estimated survival rate at 4 years was 88.8% (70% CL: 83.3-94.5). Morbidity involved three patients. One had a total heart block after operation, requiring pacemaker implantation and two patients were reoperated: one for severe autograft failure due to recurrent acute rheumatic fever and the other for severe stenosis at the distal anastomosis of the pulmonary allograft. Thromboembolic complications and endocarditis were not registered. Reoperations for technical or degenerative reasons were not necessary. The estimated event-free survival rate at 4 years was 78.7% (70% CL: 71.0-86.4). Serial echocardiography (n = 28) showed a significant increase of the autograft annulus diameter of 2.9 mm (SD: 2.7). Thirty-five of the 37 patients with an autograft in situ were in NYHA class I, and 2 in class II. At last follow-up precordial color Doppler echocardiography showed moderate aortic regurgitation in one patient and no, trivial or mild aortic regurgitation in 36 patients. Stenosis of the autograft was not observed. These medium-term results are promising with respect to mortality, morbidity and functional results.(ABSTRACT TRUNCATED AT 250 WORDS)
7527748 IgM anti-A and D SnRNP proteins and IgM anti-dsDNA are closely associated in SLE sera. 1995 Jan U1RNP and Sm precipitins occur in systemic lupus erythematosus (SLE) and in overlap syndromes, while precipitins to Ro/SSA and La/SSB occur in SLE and its variants as well as Sjögren's syndrome. In studying IgM and IgG antibodies to these polypeptides by Western blot, we found the expected frequency of antibodies to the A protein of the U1RNP specificity and the D protein of the Sm specificity in sera with precipitins to U1RNP and Sm, but also found the frequent occurrence of both IgM and IgG anti-A and D in SLE sera with no precipitins, and in sera with anti-Ro/SSA and/or anti-La/SSB precipitins, but not in sera from patients with rheumatoid arthritis, polymyositis, scleroderma, or normals. We have studied the sera which bind the A and D polypeptides on Western blot to test their ability to bind native U1RNP (which contain the A and D proteins) in ELISA. The results indicate that most anti-Ro/SSA alone, anti-Ro/SSA, and anti-La/SSB sera as well as SLE sera with no precipitins react preferentially with the denatured A and D proteins. Further study of sera with IgM anti-A and D in Western blot reveals that these sera also frequently contain anti-double-stranded DNA antibodies. These results show that the anti-A and D responses, especially IgM anti-A and D, occur not only in patients with precipitating antibodies to SnRNPs, but in almost half of patients across the lupus spectrum. The extended prevalence of antibodies to the denatured A and D proteins in Western blot is associated with the cross-reaction of antibodies to dsDNA.