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ID PMID Title PublicationDate abstract
1522240 Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to th 1992 Sep This study reports on leukemia inhibitory factor (LIF) in human articular connective tissues. Biologically active LIF is present in synovial fluids from patients with osteoarthritis and at higher titers in samples from patients with rheumatoid arthritis. Cultured human synoviocytes and articular chondrocytes produced biologically active LIF and synthesized and secreted LIF proteins that migrated in SDS PAGE at approximately 43 kD. This was increased after stimulation with IL-1 beta. Chondrocytes in serum-containing cultures expressed the 4.2-kb LIF mRNA. IL-1 beta, LPS, and to a lesser extent tumor necrosis factor-alpha induced LIF gene expression. LIF autoinduced its mRNA and this provides evidence for an effect of this cytokine on function of joint tissue cells. Among a series of growth factors tested, transforming growth factor (TGF beta), including the isoforms TGF-beta1, TGF-beta 2, and TGF-beta 3, platelet-derived growth factor, basic fibroblast growth factor, and insulin-like growth factor induced this cytokine gene but differed with respect to the duration of their effects. Cultured synoviocytes expressed the LIF gene in response to the same set of peptide regulatory factors. Analysis of signal transduction pathways showed that PMA increased LIF mRNA, whereas calcium ionophore and cAMP had no detectable effects. Cycloheximide was a potent LIF mRNA inducer and dexamethasone inhibited LIF induced by PMA or IL-1 beta. Cartilage organ cultures and synovial tissues stimulated with IL-1 expressed high levels of LIF mRNA as demonstrated by in situ hybridization. These results identify LIF as a new cytokine that is produced by joint tissue cells and is overexpressed in arthritis. The induction of this cytokine by factors that are present during joint inflammation and the effects of LIF on connective tissue cells suggest that LIF is a mediator that can contribute to the pathogenesis of arthritis.
7473485 Influence of food on the bioavailability of oral methotrexate in children. 1995 Aug OBJECTIVE: To determine the bioavailability of oral methotrexate (MTX) in patients with juvenile rheumatoid arthritis in the fasting and fed states. METHODS: Each patient randomly received their usual weekly MTX dose either orally (po) after an overnight fast, po immediately after a breakfast of their choice, or intravenously (iv) on 3 consecutive weeks. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4, and 6 h after po and 0, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 h after iv administration. RESULTS: Fourteen patients (10 female) aged 2.8 to 15.1 yrs completed the study; the results of 13 patients were evaluable. The mean elimination rate constant was 0.27 +/- 0.065, 0.26 +/- 0.067, and 0.25 +/- 0.11 h-1 after po fasting, po fed, and iv administration, respectively. The total area under the serum concentration vs time curve was 1.87 +/- 0.83, 1.50 +/- 0.51, and 1.85 +/- 0.80 mumol/l.h after po fasting, po fed, and iv administration, respectively. The maximum serum MTX concentration (Cmax) was 0.65 +/- 0.33 and 0.39 +/- 0.18 mumol/l after po fasting and po fed administration, respectively (p = 0.0022). The time to Cmax was 0.94 +/- 0.40 and 1.32 +/- 0.68 h after po fasting and po fed administration, respectively (p = 0.1464). The bioavailability of oral MTX while fasting was 1.1 +/- 0.51, while that after a meal was 0.88 +/- 0.35 (p = 0.0211). CONCLUSION: These data indicate greater oral bioavailability of MTX in the fasting state. We recommend that children receive MTX on an empty stomach.
8678893 The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline a 1996 Jul 12 A quantitative nonisotopic solution assay for gelatinases and inhibitors was developed using biotinylated gelatin as enzyme substrate. In this assay, residual biotinylated substrate is sandwiched between avidin-coated plates and streptavidin-peroxidase and is quantified by the peroxidase reaction. This assay was useful for measuring gelatinase activities and defining the activities of gelatinase inhibitors. When 23 tetracycline analogues were compared, significant differences in gelatinase B inhibition were found between various compounds. 4-epioxytetracycline base, 4-epichlortetracycline, meclocyclinesulfosalicylate, and unmodified metacycline and minocycline proved to be the most potent gelatinase B (EC 3.4.24.35) inhibitors. The gelatinase B inhibitory activity of tetracyclines was clearly dissociated from their antimicrobial activity. The effect of high-molecular-weight inhibitors, such as monoclonal antibodies, was also demonstrable in the microtiter plate assay. In view of the pathophysiological function of gelatinases, the definition of gelatinase inhibitors with known efficacy, safety, and side effects is crucial for the treatment of diseases such as rheumatoid arthritis and multiple sclerosis. Particular tetracyclines fulfil these criteria and the described assay is useful for defining other gelatinase-inhibiting lead compounds.
8761579 Raised levels of agalactosyl IgG in childhood tuberculosis. 1996 Mar Raised levels of agalactosyl immunoglobulin G (IgG) have been found in adults with tuberculosis, Crohn's disease and rheumatoid arthritis, and recent evidence, both circumstantial and experimental, suggests that it has distinct functional properties that play a role in pathogenesis. Since tuberculosis in infants is strikingly different from the disease seen in adults, but switches to the adult form at adrenarche or puberty, we documented the association of agalactosyl IgG with tuberculosis in childhood between the ages of 0 and 16 years. Sera were collected from 99 children diagnosed as cases of tuberculosis in Istanbul, Turkey, and compared with levels in non-tuberculous controls. The percentage of agalactosyl IgG was significantly raised in children with tuberculosis overall (P < 0.001, Mann-Whitney U test) and in all age groups except for children over 12 years old, whose numbers were too small to be meaningful. Therefore the differences between adult and childhood tuberculosis are not due to a difference in the tendency for agalactosyl IgG to be produced at different ages. The percentage of agalactosyl IgG may be useful for monitoring the progress of individual complicated cases.
8735354 Hormonal and non-hormonal interventions for menopausal symptoms. 1996 Mar Recent cohort studies confirm that only flushes, night sweats and vaginal dryness are provenly associated with ovarian failure. Experiments nave demonstrated that these symptoms and insomnia associated with nocturnal vasomotor symptoms are more effectively controlled by oestrogen than placebo. Hormonal interventions include a variety of oestrogen or oestrogen/progestogen regimes. Non-hormonal treatments of flushes include exercise, paced respiration and psychotherapy. After the menopause vaginal atrophy and some urinary symptoms respond to local oestrogen and vaginal dryness in also prevented by lubricants. Libido is not increased by oestrogen therapy but may be improved by testosterone. Depression is common in middle-aged women but is not specifically associated with the hormonal changes occurring at the menopause. Oestrogen therapy may improve and stabilise mood during the peri-menopause but there is no firm evidence that it is effective for depression after the menopause. Arthralgia is not a symptom specific to menopause and experimental evidence concerning the role of oestrogen in the treatment of rheumatoid arthritis is inconclusive. Cognitive function is not related to menopause and measures such as stopping smoking, exercise and maintaining body weight may be partly effective in preventing menopausal symptoms.
11082754 Low-dose methotrexate as a risk factor for Pneumocystis carinii pneumonia. 1996 Jan Low-dose methotrexate is a commonly prescribed medication for the treatment of rheumatoid arthritis and other rheumatic diseases. Its effectiveness in ameliorating the clinical symptoms and findings has been well established, and adverse effects have been relatively infrequent, particularly compared to other immunosuppressive agents. Pneumocystis carinii pneumonia is most often seen in severely immunosuppressed patients related to the acquired immunodeficiency syndrome or treatment of malignancies with potent cytotoxic agents. However, P. carinii pneumonia can occur in patients receiving low-dose methotrexate concurrent with corticosteroids, nonsteroidal anti-inflammatory drugs, renal impairment, or a combination of factors. We report 1 patient and review 10 additional cases that support this relationship.
8861587 Arthroscopically assisted arthrodesis of the ankle joint. 1996 In 26 patients we performed an arthroscopically assisted arthrodesis of the ankle. The patients' ages ranged from 31 to 69 years. The male:female ratio. Sixteen patients had posttraumatic degenerative joint disease, three patients suffered from a previous infection, four patients had rheumatoid arthritis, and three patients had an osteochondritis dissecans in their past history. The time taken for surgery ranged from 65 to 135 min. Compared with open procedures we documented less postoperative swelling and minor use of analgesics. Time of follow-up was a minimum of 6 months and a maximum of 75 months. In 22 patients we found solid fusion at the time of followup. Fusion was accomplished by 2 months postoperatively in four patients, by 3 months in nine patients, by 4 months in another six patients, and by 6 months in 3 patients. Three patients did not evidence any bony fusion, but they were free of pain. In one patient an open revision was necessary. According to our experience, we recommend arthroscopically assisted arthrodesis of the ankle in patients with degenerative joint disease without rotational or varus/valgus malalignment, severe bone defects or neuropathic disease.
8542607 Inhibition of human leukocyte elastase by chemically and naturally oversulfated galactosam 1995 Oct 23 Several samples of oversulfated chondroitin and dermatan were obtained by chemical sulfation and by SAX-HPLC enrichment. The starting products and oversulfated products were tested as potential inhibitors of human leukocyte elastase, an enzyme hypothesized to be involved in the etiology of diseases such as emphysema, atherosclerosis, and rheumatoid arthritis. Chemical oversulfation (SO3H/COOH 1.6-3.2), preferentially occurring at C-6 of galactosamine residues, was found generally to increase the inhibitory power on elastase. Chemically oversulfated galactosaminoglycans thus have potential as therapeutic agents, considering that they produce non-significant effects on the hemocoagulative system. Two naturally oversulfated dermatans sulfate (SO3H/COOH ca. 1.2), mainly oversulfated at C-2 of iduronic acid residues, showed comparatively higher anticoagulant activity (in the HC-II mediated thrombin inhibition test).
7587736 Comparison of monoclonal antibodies for flow cytometric analysis of HLA-B27 antigen. 1995 Mar 15 HLA-B27 is an antigen associated with the disease ankylosing spondylitis. Ninety percent of Caucasians with ankylosing spondylitis possess the HLA-B27 antigen. However, only 20% of Caucasians with the HLA-B27 antigen will develop the disease. Defining the presence or absence of the HLA-B27 antigen can be helpful in differentiating ankylosing spondylitis from juvenile rheumatoid arthritis. In this study, we evaluated the application of two monoclonal antibodies (MoAbs), using flow cytometric analysis for the detection of HLA-B27 antigen. After an initial comparison of HLA-B27 analysis by flow cytometry to the standard microlymphocytotoxicity assay, cutoffs were established to differentiate HLA-B27 positive from HLA-B27 negative. One MoAb showed very reliable results with > 99% accuracy in discriminating HLA-B27 positive from HLA-B27 negative samples. Various parameters were investigated to obtain the optimum results and showed that incubation time, reagent lot, and the flow cytometric instrument can affect the results. We concluded that a reliable MoAb and flow cytometry are valuable for the rapid and inexpensive determination of HLA-B27 typing in the clinical setting. However, testing conditions can affect the accuracy of results; therefore, adequate parallel testing in various conditions must be performed in order to establish the proper standards.
7553035 [Anti-platelet antibodies in sera from patients with systemic lupus erythematosus by immun 1995 Feb It has not been clarified that the anti-platelet antibodies are related to thrombocytopenia in systemic lupus erythematosus (SLE). We evaluated the presence of anti-platelet antibodies in sera from patients with SLE using immunoblot analysis. In this study, 19 of 65 cases (29.2%) in SLE had anti-platelet antibodies in their sera, whereas no anti-platelet antibodies were detected in 16 cases of rheumatoid arthritis, 16 cases of progressive systemic sclerosis, 2 cases of polymyositis-dermatomyositis and 10 healthy controls. Six bands of 200 kDa, 140 kDa, 120 kDa, 95 kDa, 80 kDa and 65 kDa molecular weight were detected using immunoblot analysis. The platelet antibodies to 95 kDa and 80 kDa proteins were frequently detected in 12.3% and 16.9% respectively of SLE. These 2 antibodies were absorbed with the platelet pellet derived from healthy person. Therefore, it was suggested that the antibodies to 90 kDa and 80 kDa platelet antigens were specific to platelet membrane protein. Although we could not find any correlation between clinical and laboratory manifestations of SLE and these platelet antibodies, these antiplatelet antibodies were specifically detected in sera from patients with SLE by immunoblot analysis.
7822331 Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha 1995 Jan 13 Retinoic acid receptors (RARs) regulate gene expression either by directly binding to the RAR-responsive elements or by antagonizing the action of c-Jun/c-Fos (AP1). AP1 is involved in the expression of metalloproteases, cytokines and other factors which play critical roles in the turnover of extracellular matrix, inflammation and hyperproliferation in diseases such as psoriasis, rheumatoid arthritis and in tumor metastases. We demonstrate here that synthetic retinoids inhibit 12-O-tetradecanoylphorbol-14-acetate-induced transcription from the stromelysin AP1 motif through RAR alpha, -beta, and -gamma. Interestingly, these diaryl acetylenic retinoids, which are potent agonists only for RAR beta and RAR gamma, but not for RAR alpha, in transactivation assays, are able to inhibit AP1-dependent gene expression through RAR alpha. Thus these analogs can differentially affect the transactivation and AP1 antagonistic functions of RAR alpha. These results demonstrate that the transactivation and AP1 antagonistic functions are separable, and it should be possible to develop retinoids that are completely specific for AP1 antagonism through all RARs. Furthermore, using an RAR-selective ligand, we also demonstrate the separation of ligand binding and AP1 antagonism functions of RARs.
8724841 Nitric oxide in infectious and autoimmune diseases. 1995 Nitric oxide (NO) is a critical mediator of a variety of biological functions. A range of micro-organisms, including viruses, bacteria, protozoa and helminths, is sensitive to NO produced by macrophages activated with gamma-interferon (IFN-gamma) and lipopolysaccharide. In contrast, NO is involved in a number of important immunopathologies, including diabetes, graft-vs-host reaction, rheumatoid arthritis, systemic lupus erythematosus, experimental autoimmune encephalomyelitis and multiple sclerosis. Thus, it is crucial that the synthesis of NO is under tight regulation. This is achieved, in part, through the opposing cytokines produced by T helper 1 (Th1) and Th2 cells. Th1 cells produce IFN-gamma, which is the most powerful inducer of inducible NO synthase (iNOS). In contrast, interleukin 4 is produced by Th2 cells and inhibits the induction of iNOS at the level of transcription. Furthermore, NO is also produced by Th1 cells, whose proliferation can be inhibited by high concentrations of NO. Thus, apart from being a mediator of Th1/Th2 interaction, NO may also be an important self-regulatory molecule that prevents the over-expansion of Th1 cells which are implicated in a range of severe immunopathologies.
8086445 Purification and secondary structural analysis of tissue inhibitor of metalloproteinases-1 1994 Sep 21 In connective tissue diseases such as rheumatoid arthritis, the matrix metalloproteinases are the primary enzymes involved in tissue degradation. Tissue inhibitor metalloproteinases-1 (TIMP-1) is a specific inhibitor of these enzymes, which is thought to regulate their action in vivo. The structure and function of TIMP-1 may therefore be important as the basis for the rational design of therapeutic agents. This paper describes a simple and effective method for the purification of sufficient quantities of TIMP-1 for spectroscopic studies. Circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopy have, together, showed TIMP-1 to be mostly in a beta-sheet conformation, with significant amounts of alpha-helix and beta-turn. Two-dimensional nuclear magnetic resonance spectroscopy indicated a correspondingly high proportion of beta-sheet. CD and FTIR have also shown TIMP-1 to have high thermostability.
7955606 Blood dehydroepiandrosterone sulphate (DHEAS) levels in polymyalgia rheumatica/giant cell 1994 Jul Blood levels of dehydroepiandrosterone sulphate (DHEAS) were measured by radioimmunoassay (RIA) in patients with: a) polymyalgia rheumatica/giant cell arteritis (PMR:TA; N = 25), with and without cortisone derivative treatment (N = 10 and N = 15, respectively); and b) primary fibromyalgia (PF; N = 15). The mean DHEAS levels were found to be significantly reduced in PMR:TA, compared to those in PF (Geom. mean 820 vs. 2300 nmol/l, respectively; p < 0.001), and the reduction was more marked in patients on cortisone derivative treatment. The DHEAS levels found in PF were found to be normal and consistent with those previously reported in non-immune mediated rheumatological diseases such as osteoarthritis, and in healthy subjects, using the same method of analysis. The low levels found in patients with PM:TA are in accordance with those previously reported in immune-mediated diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, suggesting that diminution of DHEAS is a constant endocrinologic feature in these categories of patients. The pathophysiological significance of these low DHEAS levels needs to be investigated.
8067196 [Clinical applications of erythropoietin]. 1994 Erythropoietin (EPO) is a glycoprotein produced primarily by the kidney in response to tissue hypoxia, and is the principal factor regulating red blood cell production. It stimulates erythroid precursors in the bone marrow to proliferate and mature into morphologically identifiable red blood cells. This hormone acts by binding to specific high-affinity receptor on erythroid precursors. Failure to produce adequate quantities of EPO leads to severe anemia, a situation most often encountered in patients with end stage renal disease. With the application of recombinant DNA technology, the gene for this hormone has been molecularly cloned, sequenced and expressed in a biologically active form in mammalian cells. The recombinant EPO has been demonstrated to correct anemia in patients with severe end stage renal disease and alleviate their transfusion requirements. It has also been studied for anemia associated with HIV infection/zidovudine therapy, in cancer, rheumatoid arthritis, and prematurity. In addition it has been studied as a facilitator of autologous blood predeposit in patients scheduled for elective surgery and as a perisurgical adjuvant to hasten hematologic recovery and possibly avoid the need for homologous transfusion after elective surgery. When administered with the current guidelines EPO appears to be safe drug with favorable risk/benefit ratio.
7849104 Effects of plasminogen and interleukin-1 beta on bone resorption in vitro. 1994 Inflammatory bone resorption, a characteristic feature of periodontal disease and rheumatoid arthritis, appears to be mediated by interleukin-1 beta (IL-1 beta). IL-1 beta has been shown to stimulate a wide range of proteolytic enzymes, including collagenases and plasminogen activators, in particular chondrocytes, synovial cells, and isolated osteoblasts. In this study, we have examined the hypothesis that IL-1 beta may stimulate bone loss by inducing the activity of plasminogen activators (PAs) in bone cultures. The latter would convert plasminogen to plasmin, which in turn can activate precursor procollagenase to collagenase. Active collagenase would then break down the bone collagen matrix. In the present study, release of 45Ca from fetal rat long bones in culture was studied in the presence of plasminogen and IL-1 beta. Plasminogen and IL-1 beta separately enhance resorption of fetal rat long bones in vitro. When plasminogen and IL-1 beta are added together at suboptimal levels, mainly additive effects are observed. The presence of heat-inactivated serum does not alter these results. These data tend to indicate that IL-1 beta is stimulating bone resorption through both PA-dependent and PA-independent pathways.
8120859 Noncontraceptive benefits of oral contraceptives. 1993 Dec The noncontraceptive health benefits of oral contraceptives were initially summarized a decade ago. Studies conducted in the last decade confirmed the findings of earlier studies with high-dose oral contraceptives and extended them to low-dose formulations. Among the noncontraceptive health benefits first cited were reductions in menorrhagia, irregular menses, endometrial cancer, ovarian cancer, functional ovarian cysts, benign breast disease, dysmenorrhea, premenstrual tension and iron-deficiency anemia. In addition, women who used oral contraceptives were less likely to develop rheumatoid arthritis or acute salpingitis, particularly moderate or severe forms, than were women using no method of contraception. Despite the fact that such benefits were identified more than 10 years ago and despite their inclusion in oral contraceptive labeling, women today are largely unaware of the noncontraceptive health benefits associated with oral contraceptive use.
8251150 Autoimmunity in schizophrenia: a review of recent findings. 1993 Oct The pathophysiology of psychotic and other symptoms in schizophrenia remains a mystery despite decades of research. Even though it has been suspected for many years that autoimmune mechanisms may play a role in the pathophysiology of schizophrenia, firm evidence for this hypothesis has been lacking. Our studies, over the last 10 years, have revealed that a subgroup of schizophrenics have several significant immunological abnormalities, including increased prevalence of autoimmune diseases and of antinuclear antibodies (ANA) and anticytoplasmic antibodies (ACA), decreased lymphocyte interleukin-2 (IL-2) production, increased serum IL-2 receptor concentration, increased serum IL-6 concentration, and an association with HLA antigens. These findings are characteristic of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis and insulin-dependent diabetes mellitus. We also found that some schizophrenics have antibodies to hippocampal antigens (AHA) in their serum, together with lowered IL-2 production. None of the above findings can be interpreted as definitely confirming the role of autoimmunity in schizophrenia. Nevertheless, taken together, the recent evidence points towards the existence of a subgroup of schizophrenics who have immunological findings consistent with that hypothesis. Further studies directed at finding the brain antigens targeted by the immune system in these patients, and longitudinal studies correlating clinical and immune changes over time, are needed.
8331406 Posterior atlantoaxial facet screw fixation. 1993 Aug Eighteen patients with atlantoaxial instability were treated with posterior atlantoaxial facet screws to obtain immediate rigid fixation of C1-2. Of these 18 patients, instability occurred due to trauma in nine, rheumatoid arthritis in six, neoplasms in two, and os odontoideum in one. Four patients presented with nonunion after failed C1-2 wire and graft procedures. In all cases in this series the screw fixations were augmented with an interspinous C1-2 strut graft which was wired in place to provide three-point stabilization and to facilitate bone fusion. In every case fixation was satisfactory, and C1-2 alignment and stability were restored without complications due to instrumentation. One patient died 3 months postoperatively from metastatic tumor; the spinal fixation was intact. All 17 surviving patients have developed osseous unions (mean follow-up period 12 months, range 6 to 16 months). Posterior atlantoaxial facet screw fixation provides immediate multidirectional rigid fixation of C1-2 that is mechanically superior to wiring or clamp fixation. This technique maximizes success without the need for a supplemental rigid external orthosis, and is particularly useful for pseudoarthrosis.
8505412 Advances in the understanding and treatment of multiple sclerosis. Boston, Massachusetts, 1993 May Basic and applied research on multiple sclerosis (MS) has become increasingly focused on the development and testing of new therapeutic agents for this devastating disease. After a generation or more of exposing patients to non-specific immunoregulatory and other agents that have been, at best, of minimum benefit and significant potential or actual toxicity, attention has turned to attempts to identify treatment modalities that might be used in a more specific, effective and safe fashion. This trend has not been lost on the emerging biotechnology industry, which tends to view MS as both a disease to be explored on its own and as a disease whose solution may also open doors into other chronic diseases of purported autoimmune etiology, such as rheumatoid arthritis, type I diabetes, and others. These trends toward an increasing biotechnological approach to MS, coupled with an academic and industrial focus on the disease, were the clear motivations behind a recent two-day conference entitled "Advances in the Understanding and Treatment of Multiple Sclerosis" held in Boston and sponsored by a commercial meeting planner, International Business Communications USA Conferences, Inc.