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ID PMID Title PublicationDate abstract
9007518 Potent inhibition of angiogenesis by wortmannin, a fungal metabolite. 1996 Dec 27 Wortmannin ([1S-(1 alpha, 6b alpha, 9a beta, 11 alpha, 11b beta)]-11-(acetyloxy)-1,6b,7,8,9a,10,11,11b-octahydro-1- (methoxymethyl)-9a, 11b-dimethyl-3 H-furo[4,3,2-de]indeno[4,5-h]-2-benzopyran-3,6,9-trione), a fungal metabolite that is as a selective inhibitor of phosphatidylinositol 3-kinase, was evaluated for its potential as an inhibitor of in vivo angiogenesis in a bioassay system involving growing chick embryo chorioallantoic membranes. It showed dose-dependent inhibitory activity against embryonic angiogenesis. This inhibition occurred at a dose as low as 1 ng (2.3 pmol) per egg and the ID50 value was 30 ng/egg. These findings suggest that wortmannin is a new angiogenesis inhibitor, and that it may be a lead antibiotic for a novel class of therapeutic agents for angiogenesis-dependent diseases like cancer, diabetic retinopathy and rheumatoid arthritis.
8954913 Treatment of fibroblast-like synoviocytes with IFN-gamma results in the down-regulation of 1996 Dec 13 In an effort to isolate genes that change expression at the mRNA level during treatment of fibroblast-like synoviocytes (SFC) with IFN-gama, we performed a differential display analysis. Here, we report the isolation of a cDNA clone corresponding to a 3.1 kb mRNA species that is reduced in synoviocytes after culture with IFN-gama. Sequence analysis revealed the 211 bp length cDNA clone to be identical to the motility-stimulating 125 kDa protein autotaxin (ATX). The down-regulation of ATX mRNA was confirmed by Northern blot analysis as well as competitive RT-PCR. SFC express 1 ng ATX mRNA/microgram total RNA. IFN-gama down-regulated ATX mRNA up to 50% as compared to control. Our results add a new finding to the manifold functions described for IFN-gama in rheumatoid arthritis.
8941363 Human BST-1 expressed on myeloid cells functions as a receptor molecule. 1996 Nov 21 We have previously identified and cloned BST-1 as a molecule which is overexpressed on the bone marrow stromal cell lines derived from patients with rheumatoid arthritis and which has the ability to support the pre-B cell growth. BST-1 is a glycosylphosphatidylinositol-anchored ectoenzyme having ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities. In this report, we demonstrate that human BST-1 was expressed on monocytes, granulocytes in the peripheral blood of healthy donors, and macrophages matured in vitro. Cross-linking of BST-1 with a polyclonal anti-BST-1 antibody induced tyrosine phosphorylation of a 130-kDa protein (p130) in the human myeloid cell lines U937 and THP-1. Cross-linking of BST-1 overexpressed on a transfectant induced tyrosine phosphorylation of p130, dephosphorylation of the 100-kDa protein, and growth inhibition. These results suggest that BST-1 can deliver signals into cells and function as a receptor.
8796974 Actions and toxicity of nonsteroidal anti-inflammatory drugs. 1996 May Use of nonsteroidal anti-inflammatory drugs (NSAIDs) continues to be an important therapeutic intervention throughout the world for patients with pain and inflammation. The six major classes of NSAIDs (including the salicylates) bear the common property of inhibiting cyclooxygenase, the enzyme that catalyzes the synthesis of cyclic endoperoxides from arachidonic acid to yield prostaglandins. Anecdotal evidence has accumulated that the nonacetylated salicylates are as efficacious as the other NSAIDs, but there have been few controlled trials demonstrating that they are reasonable anti-inflammatory agents. This paper discusses the newest of the available clinical observations that nonacetylated salicylates are as efficacious as one of the newer NSAIDs in patients with rheumatoid arthritis. Because the nonacetylated salicylates are weak prostaglandin inhibitors, several other non-prostaglandin mediated mechanisms of action for the NSAIDs have been postulated and are described in this paper. In addition to papers describing NSAID effects on cartilage, this year several interesting papers described further effects of tenidap, a novel NSAID presently in development. Other papers reviewed attempts to develop NSAIDs with less severe gastrointestinal effects. Some reports discuss the use of topical NSAIDs, which are not clearly better than oral preparations. Data are also reviewed demonstrating that misoprostol effectively decreased significant poor gastrointestinal outcomes in patients who were treated with this NSAID for 6 months. New treatment regimens for decreasing misoprostol-induced toxicity are also reviewed. Finally, the effects of NSAID prophylaxis in preventing heterotopic bone formation in patients with osteoarthritis who undergo hip replacement surgery are noted.
8835356 Different genotypes of human polyomaviruses found in patients with autoimmune diseases in 1996 Feb We have assayed for the presence of human polyomaviruses in urine of autoimmune disease patients, such as systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), rheumatoid arthritis (RA), or dermatomyositis/polymositis (DM/PM), by PCR. The results indicate that approximately 40% of patients were JCV positive and 15% of the JCV positive patients were also infected by BKV at the same time according to Southern blot and DNA sequencing of the PCR products. Interestingly, the JCV present in autoimmune diseases patients were Taiwan-1, Taiwan-2, and Taiwan-3 strains with pentanucleotide-A (GGGAA) and/or -B (AAAGC) deletions within the regulatory region. In addition, BKV found in the examined samples were Taichung-1 and Taichung-2 strains. Taichung-1 had two nucleotide alterations and Taichung-2 had six nucleotide differences within the regulatory region when compared to WW BKV archetype. Although the examined autoimmune diseases patients included RA, SLE, PM, DM, and SS patients, there appears to be no correlation between disease and virus strains. However, Taiwan-2 strain JCV with two copies of pentanucleotide-A deletion was present in the patient with the longest period of immunosuppressive medication.
8918749 Immunological disorders in C virus chronic hepatitis. 1996 Hepatitis C virus infection can be accompanied by a number of systemic, non-specific or autoimmune disorders and by extra-hepatic biological abnormalities. Their exact prevalence remains to be determined, together with their association with certain pathologies such as non-Hodgkin lymphoma. The most frequent biological peculiarity is cryoglobulinaemia, found in more than 50% of patients. It is only symptomatic in less than one-third of cases (as purpura, Raynaud's syndrome, neuropathy or renal failure), and could be the origin of benign lymphoproliferative haematological pathology, then of a malignant one (non-Hodgkin lymphoma). Rheumatoid arthritis may develop in 20-25% of cases. Periarteritis nodosa is a rare but possible occurrence. Autoimmune disorders proper include hepatitis with anti-LKM1 antibodies, thyroiditis, skin manifestations, complex connectivitis and Gougerot-Sjögren's syndrome. This syndrome is histologically detected in 15-50% of patients. It affects women preferentially and is usually not accompanied by anti-SSA or anti-SSB antibodies. Thyroidites are different from those occurring under Interferon-alpha therapy, and should be systematically investigated before initiating that therapy. Lichen planus can be associated to HCV infection. The proven induction of autoimmune disorders by Interferon therapy requires that immune disorders be fully assessed before treatment initiation, and close monitoring for their occurrence is necessary throughout the treatment course. TSH and thyroid hormone in particular should be closely monitored.
9420181 Low fat diet decreases alpha-tocopherol levels, and stimulates LDL oxidation and eicosanoi 1995 Nov 17 The effects of a conventional 1000 kcal diet, and of a further restriction of dietary fat by a fat substitute, on the concentrations of vitamin A and E in plasma and LDL, the formation of lipid peroxides and eicosanoids were investigated in 10 obese volunteers. In vitro copper catalyzed oxidation of conjugated dienes, lipid peroxides and TBARS activity, measured in LDL samples after week 2 (supplementation with 140 mg/d alpha-tocopherol and 5000 IU retinol-acetat for two weeks), week 6 (conventional diet) and week 10 (fat substitute), increased with vitamin E depletion statistically significant after week 10 compared to the values after week 2. Concomitantly, PGE2 and LTB4, determined by RIA, increased to 344% and 166%, respectively, compared to the values after week 2. PGM, determined as tetranorprostanedioic acid by GC-MS, increased to 120%. Stimulation of lipid peroxidation and eicosanoid formation was more pronounced in persons with initially low (19 - 26 micromol/l plasma) than in those with high (37 - 70 pmol/l plasma) concentrations of alpha-tocopherol. We conclude that fat restricted diets can lead to an unwanted stimulation of lipid peroxidation and eicosanoid formation, which may be relevant in states of disease, e. g. arteriosclerosis or rheumatoid arthritis.
8579980 Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing con 1995 Nov Connective tissue diseases (CTDs) frequently present with one or only a few symptoms, which does not allow prompt diagnosis. Raynaud's phenomenon is one of those symptoms. However, only a minority of patients who present with Raynaud's phenomenon develop a CTD. Prognostic factors for the future development of CTD in such patients are older age at presentation, more severe Raynaud's phenomenon, the presence of antinuclear antibodies, and abnormal patterns on nailfold capillary microscopy. Some patients have overlapping symptoms of various CTDs. Mixed connective tissue disease (MCTD) is the prototype of such an overlapping syndrome. However, during follow-up, most patients with MCTD develop a specific CTD, either scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or combinations of those illnesses. Primary pulmonary hypertension is one of the leading causes of death in MCTD. Its treatment is insufficient, although continuous prostacyclin infusion may provide some relief. New therapies such as nitric oxide and combined heart-lung transplantation in an early stage should be explored. The autoimmune response to small nuclear ribonucleoproteins, which is highly characteristic for MCTD, interestingly shows cross-reactivity with retroviral antigens, and the cooccurrence of human T cell lymphotropic virus type I and HIV infection with MCTD has been reported. This suggests that those viruses, possibly by molecular mimicry, play a role in the induction of the disease. Fibrotic conditions related to silicone exposure still evoke much interest. However, most recent data do not substantiate a role for silicone gel breast implants in the development of autoimmune CTDs.
8137544 Anti-neutrophil cytoplasmic antibodies (ANCA) in inflammatory bowel disease: characterizat 1994 Mar ANCA were detected by indirect immunofluorescence in 34 out of 67 patients with ulcerative colitis (UC, 51%) and in 14 out of 35 patients with Crohn's disease (CD, 40%). All but one ANCA-positive sera produced a perinuclear pattern of fluorescence (P-ANCA) on ethanol-fixed neutrophils. On paraformaldehyde-fixed neutrophils 76% of P-ANCA-positive sera in UC and 50% of P-ANCA-positive sera in CD produced cytoplasmic fluorescence, indicating that, indeed, cytoplasmic antigens are recognized by a considerable number of these sera. By Western blot analysis using whole neutrophil extract as a substrate 46% of sera from patients with UC and 32% of sera from patients with CD showed reactivity with either lactoferrin, polypeptides occurring as a doublet of 66/67 kD mol. wt, or polypeptides occurring as a doublet of 63/54 kD mol. wt, respectively. Identical patterns of reactivity have been observed among P-ANCA-positive sera from patients with autoimmune liver disease and rheumatoid arthritis. These data suggest that ANCA of restricted specificities are not specific for inflammatory bowel disease (IBD), but are present in diverse conditions characterized by chronic idiopathic inflammation.
8178053 [Human major histocompatibility complex: the HLA system]. 1994 Jan 1 The HLA (human leukocyte antigens) system, or human major histocompatibility complex, is the most polymorphic functional genetic entity known at present. It consists of HLA class I genes and molecules (A, B and C) which control CD8+ cell-mediated antiviral responses, and class II genes and molecules (DR, DQ and DP) which control CD4+ cell responses (anti-bacterial and anti-toxin). HLA molecules function by presenting antigenic peptides to CD8+ cells (class I) and CD4+ cells (class II). Antigen presentation depends on the intracellular location of the antigen. Antigens present in the exocytosis pathway are presented by class I molecules, while class II molecules present antigens associated with the endocytosis pathway. More than 200 alleles have been detected by means of serological testing (microlymphocytotoxicity) and biochemical methods (IEF) in the HLA class I system, and now by means of molecular biology techniques for class II molecules (PCR-SSO and PCR-RFLP). This molecular typing has revealed the amino acids in HLA molecules that confer genetic susceptibility or resistance to numerous HLA-associated diseases. This is the case for example of ankylosing spondylitis (region 45-46 of HLA-B27 molecules), juvenile diabetes (aa 57 of D beta Q) and rheumatoid arthritis (aa 65-71 of DR beta). Thus, the HLA system is a genetic tool for diagnostic and therapeutic decision-making.
8152201 [Clinical applications of cytokines in pediatrics]. 1994 Jan Cytokines are decisive for the regulation of the immune system as well as the renewal and maturation of the haematopoietic cells. The most important groups of substances, several of which are already produced by gentechnology, are the interferons, the interleukins and the haematopoietic growth factors. The main indications for the application of alpha-(less often beta-)Interferon in children are the juvenile larynx papillomatosis, chronic hepatitis B, viral encephalitis, and also chronic myeloic leukemia, extended haemangiomas, recurrent Langerhans cell histiocytosis and nasopharynx carcinomas. gamma-Interferon is administered successfully for chronic granulomatous disease and has recorded positive effects in therapy resistant rheumatoid arthritis, in kidney cell carcinoma and in osteopetrosis. G-CSF, GM-CSF and Interleukin 3 are the most effective haematopoietic growth factors currently in use. Through G-CSF congenital agranulocytosis (Kostmann syndrome) has become a treatable disease. Other proven applications are in the reduction of aplastic phases after chemotherapy and in critical situations of primary bone marrow failure as well as myelodysplastic syndromes, for prevention of transplant rejections after bone marrow transplantation and for mobilisation of stem cells into peripheral blood before apheresis. Erythropoietin is established in the treatment of chronic renal anaemia and is currently used in the treatment of anaemia in preterm infants. Finally, Interleukin 2 is also used for adoptive immunotherapy in children with minimal residual tumors. The future will show us, whether the spectrum of indications will expand and whether a definite benefit for sick children will result from a wider application of these substances. As long as the cost/benefit ratio for certain indications is not clear, the use of these drugs should be tested in prospective studies.
8132212 A longitudinal study of per cent agalactosyl IgG in tuberculosis patients receiving chemot 1994 Jan An increased percentage of circulating IgG molecules that lack galactose from the oligosaccharides on the CH2 domain correlates with disease severity in tuberculosis, rheumatoid arthritis and Crohn's disease. We have recently observed that a single injection of 10(9) autoclaved Mycobacterium vaccae given to tuberculosis patients 7 days after the initiation of chemotherapy causes accelerated clinical improvement, and clearance of bacilli from the sputum. We now show that this immunotherapy also causes rapid loss of agalactosyl IgG, detectable within 14-21 days, whereas chemotherapy alone causes agalactosyl IgG to rise further for up to 2 months. There is simultaneous inhibition of the antibody response to lipoarabinomannan, and transient enhancement of the tuberculin skin-test response. These findings are compatible with a shift from antibody production towards increased cell-mediated immunity. The ideal treatment for tuberculosis would supplement a truncated course of chemotherapy with an immunotherapeutic preparation able to down-regulate the Koch phenomenon and replace it with an efficiently bactericidal mechanism. We tentatively postulate that a fall in per cent agalactosyl IgG [%Gal(0)] in tuberculosis patients may be a marker of such a change.
7631987 [Cutaneous reactions to gold salts]. 1994 OBJECTIVE: Evaluate the clinical features of skin reactions to gold salts. INTRODUCTION: Gold dermatitis is described in the literature as a group of reactions non-specifically associated with these drugs. PATIENTS AND METHODS: Ten patients (7 males, 3 females, mean age 59.6 years [corrected] with a skin reaction were studied over a 6 year period. All were treated with Allochrysine for rheumatoid arthritis (n = 8), rhizomelic pseudopolyarthritis (n = 1) or arthropathic psoriasis (n = 1). RESULTS: The delay to the first signs was from 2 weeks to 8 months. Three lichenoid eruptions (including two with buccal lesions and two which followed an autonomous course), 2 pityriasis rosea (one with eosinophilia and one with liver disease), 2 eczematoid dermatoses and one urticaria were observed. Pathology examinations (8/10) were in agreement with clinical diagnosis. Imputability was 14 (1 case), 13 (8 cases) and 12 (1 case). DISCUSSION: The clinical features observed were variable and in agreement with a particular clinical situation. They were not specific to gold salts and cannot be qualified as "gold dermatitis". Two autonomous and severe lichenoid eruptions were observed. Generalized lesions were associated with biological signs. This situation must be considered as a marker of severity.
8330928 Copper-dependent antioxidase defenses in inflammatory and autoimmune rheumatic diseases. 1993 Jun Gel-filtered sera of patients with various inflammatory and autoimmune rheumatic diseases (N = 354) were screened for the presence of the inflammation marker Cu-thionein. The concentrations of Cu-thionein were significantly diminished in patients with connective tissue diseases (P < 0.001). Sera of patients suffering from inflammatory rheumatic diseases were almost totally depleted of this low-molecular-weight copper protein that exerts pronounced superoxide dismutase activity and scavenges effectively hydroxyl radicals and singlet oxygen. Cortisone treatment of patients with rheumatoid arthritis, systemic lupus erythematosus, and polymyalgia rheumatica replenished impressively the serum concentration of Cu-thionein. The partial oxidation of the EPR-silent Cu(I)-chromophore to Cu(II)/Cu(I)-thionein, which is essential for the catalytic dismutation of superoxide, was monitored by electron paramagnetic resonance in the presence of activated neutrophils and monocytes. Release of Cu-thionein during the oxidative burst of peripheral blood monocytes was demonstrated in vitro. The role of prooxidant-antioxidant imbalances in the pathogenesis of rheumatic diseases is discussed.
8472358 Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I 1993 Apr We developed a radioimmunoassay (RIA) for the carboxy-terminal telopeptides of type I collagen (ICTP), cross-linked with the helical domain of another type I collagen molecule, after isolation from human femoral bone. The cross-linked peptide was liberated by digesting insoluble, denatured bone collagen either with bacterial collagenase or with trypsin, and purified by two successive reversed-phase separations on HPLC, with monitoring of pyridinoline-specific fluorescence. The purity of the peptide was verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and its origin in the type I collagen fibers was determined by amino-terminal amino acid sequencing. Polyclonal antibodies and a separation reagent containing second antibody and polyethylene glycol are used in the RIA. An immunologically identical, somewhat larger antigen is present in human serum; its concentration increases in multiple myeloma and in rheumatoid arthritis. The ICTP antigen seems to be cleared from the circulation by the kidneys, because glomerular filtration rates that are two-thirds of normal or less are associated with increased circulating ICTP concentrations. The CVs of the method are between 3% and 8% for a wide range of concentrations. The analysis of 40 serum samples can be completed in 4 h.
8456628 The role of alpha-1-protease inhibitor (A1PI) in the inhibition of protease activity in hu 1993 Alpha-1-protease inhibitor (A1PI) is the most abundant serum protease inhibitor, exhibiting inhibition of proteases known to act in osteoarthritis (OA) and rheumatoid arthritis. We have previously purified and sequenced A1PI synthesized by human articular cartilage and demonstrated in vitro protection from IL-1-induced proteoglycan (PG) degradation at a concentration of 1 mg/ml. In this study, the chondroprotective role of A1PI and possible inhibition of protease activity in OA, IL-1 and LPS-induced and aged normal human knee articular cartilage was investigated by immunohistochemical and in vitro methods. A variable low response to PG-degradation induction and to added A1PI protection of aged normal and OA cartilages was noted, while there was decreased constituative A1PI noted in OA cartilages as compared to normal.
7685684 Diclofenac/misoprostol vs diclofenac/placebo in treating acute episodes of tendinitis/burs 1993 This was a double-blind study designed to compare the efficacy and tolerability of diclofenac/misoprostol and diclofenac in patients with acute tendinitis/bursitis of the shoulder. Diclofenac 50mg/misoprostol 200 micrograms (n = 185) or diclofenac 50mg (n = 187) was administered twice or 3 times daily for 14 days. Various physician's and patient's assessments performed during and at the end of treatment showed similar improvements with both treatments. Abdominal pain, nausea and vomiting occurred somewhat more frequently with diclofenac/misoprostol, but patient withdrawals due to adverse events did not differ markedly between the groups. Thus, in the short term treatment of acute tendinitis/bursitis of the shoulder diclofenac/misoprostol possesses efficacy similar to that with diclofenac alone and provides the gastroprotective benefit of misoprostol. Previous studies in osteoarthritis and rheumatoid arthritis have established diclofenac/misoprostol to be as effective as diclofenac but with significantly less gastrointestinal damage (Verdickt et al. 1992).
1360861 Effect of sulphasalazine on antibody response to oral antigen. 1992 Dec Cholera toxin was orally administered to mice concurrently receiving sulphasalazine (SASP) dissolved in L-lysine, or a control substance (L-lysine alone). Circulating antibodies to cholera toxin of IgM, IgG and IgA class were determined by direct ELISA at day 7, 14, 21 and 28. Although both groups made a significant antibody response to the antigen, mice receiving SASP tended to produce lower levels. These were significant for IgA on day 21 (P = 0.013), and for days 7-28 (P = 0.009), and 14-28 (P = 0.007). Overall, considering all antibody classes together from day 7 to 28, there was a significant effect in the SASP treated group (P = < 0.04). It appears that SASP exerts a mild immunomodulatory effect on the mucosal immune system. Further work is obviously required to substantiate these findings. The effect on the gut mucosal immune system of a drug known to ameliorate rheumatoid arthritis may offer an insight into the aetiopathogenesis of this disease.
1592127 Aetiology of chronic leg ulcers. 1992 May This study was undertaken to determine the relative prevalence of the factors causing chronic ulceration of the leg in the general population. Two hundred and fifty-nine patients with chronic ulceration of the leg were found on screening a Western Australian population of 238,000. (The prevalence of chronic ulceration of the leg was 1.1 per 1000 population.) Two hundred and forty-two of these patients (93%) with 286 chronically ulcerated limbs were fully assessed to determine the factors contributing to ulceration. In 239 limbs (84%) ulceration involved the leg; in these limbs venous disease was the most prevalent cause of ulceration (160 limbs). Arterial disease was found in 66 limbs, with both venous and arterial disease present in 35 limbs. Rheumatoid arthritis was a causative factor in 27 limbs and diabetes was found with 29 limbs with ulceration involving the leg. In 47 limbs (16%) ulceration was confined to the foot; arterial disease (35 limbs) and diabetes (23 limbs) were the most prevalent causes of ulceration in these limbs. Venous disease was infrequent (three limbs). No disorder of the circulation was found in 48 limbs (20%) with ulceration involving the leg, and in 58 (20%) of all ulcerated limbs. More than one aetiological factor was present in 93 limbs (33%). A cause for ulceration was not found in 10 limbs (3.5%).
1579804 Immunohistochemical and functional studies of glycoprotein 60 (gp60) in platelets. 1992 We showed by immunofluorescence, immunoelectron microscopy and Western blot analysis that the plasma glycoprotein (gp60), an Fc gamma binding protein which inhibits complement-mediated prevention of immune precipitation, is present in platelets. The gp60 content of platelets in normal individuals and patients with rheumatoid arthritis was similar (mean 0.028 and 0.024 fg/platelet respectively). Immunoelectron microscopic studies showed that gp60 was present in the cytoplasm and the surface connecting structures but not in the alpha granules, dense granules or lysosomes. Using this technique gp60 was also found on platelet membranes, an observation which was confirmed by immunofluorescence. Activation of platelets with thrombin, calcium ionophore, and immune complexes (IC) resulted in the release of the contents of the alpha granules (beta-thromboglobulin), dense granules (5-hydroxytryptamine) and lysosomes (beta-glucuronidase) but did not induce gp60 secretion. The inability of Fab anti-gp60 to inhibit IC-mediated platelet aggregation and of F(ab')2 anti-gp60 to produce platelet aggregation suggested that IC-mediated platelet aggregation did not occur as a result of the interaction of IC with platelet gp60. However, as the preincubation of IC with purified gp60 produced dose-dependent inhibition of the ability of IC to aggregate platelets it is possible that fluid-phase plasma gp60 modulates the interaction of IC with platelets.