Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 1849281 | Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. | 1991 Apr 1 | The osteoclast is unique in its ability to resorb bone, and excessive osteoclastic activity has been implicated in osteoporosis, Paget disease of bone, rheumatoid arthritis, and the growth of metastases in bone. The activity of this cell is controlled by the main circulating inhibitor, calcitonin, in association with locally produced modulators. We show that nitric oxide (NO) may be an important member of the latter group. NO is produced by the vascular endothelium and nervous system and is involved in both neurotransmission and the regulation of blood pressure. However, our results show that the autocoid is also a potent inhibitor of osteoclast function. NO (30 microM) produced a decrease to approximately 50% of the original osteoclast spread area. Similar effects were also produced by 3-morpholinosydnonimine or sodium nitroprusside, reagents that spontaneously release NO. These shape changes were associated with a reduction of bone resorption after a 24-hr incubation of isolated osteoclasts on devitalized bone slices. NO is thought to act by stimulating guanylate cyclase, with a consequent increase in cyclic GMP, but a different mode of action is likely in the osteoclast since dibutyryl or 8-bromo cyclic GMP have no effect. It should be noted that calcitonin can produce similar changes in shape and activity but is associated with an increase in osteoclast intracellular calcium and cessation of membrane movement; neither of these is produced by NO, suggesting that its mode of action is different. The abundance of NO-producing endothelial cells in bone marrow and their proximity to osteoclasts suggests that marrow endothelial cells may play a physiological role in the regulation of osteoclastic activity. | |
| 2093444 | New approaches for antirheumatic therapy. | 1990 Dec | New approaches for antirheumatic therapy are firmly based on current knowledge of immunopathogenic processes. Specific immunotherapy is directed at the treatment of the disease per se and not the production of generalized immunosuppression with its unwanted side-effects. The three targets against which specific immunotherapy is directed are the T cell receptor, the HLA antigen linked to the disease and the antigenic peptide involved in the initiation and/or persistence of the disease. Therapies directed against lymphokines, monokines and cytokines produced during the chronic immune-mediated inflammation are also being developed but they may be unsuccessful not only because of the great redundancy inbuilt into the inflammatory response but also because they would produce too general a response with possibilities of harmful side-effects. Specific immunotherapy at present is largely through the use of monoclonal antibodies directed against a variety of T cell membrane antigens such as CD4, CD7 and the interleukin 2 receptor. A possible therapy is monoclonal antibodies, directed against the HLA molecule involved in the aetiopathogenesis of disease. The use of disease-causing T cell lines or clones as vaccines or therapeutic agents has solid experimental support and studies are in progress in patients with rheumatoid arthritis using T cell lines grown from synovial fluid aspirates. If successful, such therapy could be modified to the use of short peptide fragments from the relevant T cell receptor. T cells recognize antigenic peptides presented on the surface of antigen-presenting cells within a groove formed by the HLA molecule. Displacement of disease-inducing antigenic peptides by engineered 'neutral' peptides could offer a very precise form of immunotherapy. Many of these approaches are based on the hypothesis that transient but effective switching-off of the disease process may allow immunoregulatory circuits, as yet poorly defined, to come into play to permanently cure the disease. Many such therapies are in the offing. It may be that they have to be used in various combinations in order to achieve cure. For this complex and time-consuming task to attain that desired consummation, co-operative interaction between many clinicians, basic scientists and patients will be required. It is to that cooperation that we dedicate this chapter on new approaches for antirheumatic therapy. | |
| 2692695 | The benefits of combined oral contraceptives. | 1989 Nov | ||
| 2673607 | Clinical pharmacokinetics of iron preparations. | 1989 Aug | The principle of iron conservation is the basis of iron metabolism; the normal basal loss of iron from the body is about 1 mg daily in a 70 kg man and 0.8 mg in a 55 kg woman. Iron is lost mainly by the menstrual and gastrointestinal routes. The total iron requirement during pregnancy is 800 mg; in the last month the requirement may amount to 7 to 8 mg/day. Supplementary iron is recommended for many menstruating women, and during the latter part of pregnancy. Correct fetal iron metabolism is ensured by proper maternal iron status, although there are contradictory opinions and findings about the relationship between maternal and fetal iron metabolism. Preterm infants fed on breast milk have a negative iron balance, and require an iron intake of about 0.6 mg/kg/day, and 3.4 mg/1 g haemoglobin, to compensate for intestinal and venesection iron losses, respectively. The absorption of supplementary iron by the preterm infant is a linear function of intake. Preterm infants do not require iron supplements when given repeated blood transfusions. During lactation the total iron losses of the mother are 1 mg/day, and thus no supplementary iron is needed if the iron metabolism has been in balance during the pregnancy. Serum ferritin concentration decreases continuously when iron stores in the body are reduced, and totally empty iron stores are the only known reasons for low serum ferritin concentration. Despite depleted iron stores, serum ferritin concentration can be normal or higher than normal in protein-energy malnutrition, up to 3 months after major surgery, in acute liver damage, in some patients with prolonged hyperglycaemia due to diabetes mellitus, in acute lobar pneumonia, active pulmonary tuberculosis and rheumatoid arthritis on gold therapy, in sepsis secondary to marrow hypoplasia induced by chemotherapy, in heavy drinkers and for a few days after myocardial infarction. In haemochromatosis, iron is deposited in liver (producing fibrosis), pancreas, endocrine glands and heart. The rise in the level of iron in the body is due to increased absorption and/or increased intake. This pathology may occur in transfusions, in alcoholism (especially when alcoholic beverages are contaminated with iron and the diet is low-protein), in several liver diseases, in congenital transferrin deficiency and in idiopathic disease. Patients susceptible to haemochromatosis should receive a low-iron diet. Serum ferritin determination may be helpful in early identification of susceptible members of a family with idiopathic familial haemochromatosis, but transferrin saturation is not a good indicator of either iron depletion or iron overload.(ABSTRACT TRUNCATED AT 400 WORDS) | |
| 2692125 | Are retroviruses involved in the pathogenesis of SLE? Evidence demonstrated by molecular a | 1989 | High molecular weight DNA of up to 20 kbp and, additionally, an RNase-insensitive RNA of more than 60 b were isolated from plasmapheresis fluids taken from patients with active systemic lupus erythematosus (SLE). Similar nucleic acids could not be demonstrated in the plasma samples from patients with Waldenstroem's disease, rheumatoid arthritis, myasthenia gravis, and other diseases including active systemic disorders. The purified nucleic acids were analyzed in several ways; they proved to be immunogenic by inducing polyclonal and monoclonal antibodies to natural DNA as well as to synthetic polynucleotides (e.g. polyguanylic acid) after injection into experimental animals (rabbits or mice respectively). Biochemical and molecular cloning analysis of the DNA revealed features like high levels of CpG-dinucleotides, usually not observed in common human DNA. A possible exogenous origin was substantiated by comparative sequence studies of cloned plasma DNA, which showed homologies to human retroviruses, e.g. PL1 (85%/60 b) and the sequences of the gag and pol genes of human immunodeficiency virus type I (85%/157 b). Experiments applying isolated plasma nucleic acids in transfection experiments showed the induction of morphological changes in an EBV-immortalized B-cell line drawn from a healthy human donor, such as vacuolization and syncitia formation. Northern blot analysis demonstrated, exclusively in the transfected cell line, the expression of mRNA homologous to the cloned plasma DNA. Using this clone as a probe, homologous sequences could be demonstrated by Northern blot analysis in EBV-immortalized cell lines from SLE patients only and, by means of DNA amplification, in peripheral blood lymphocytes from SLE and AIDS patients.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 3115869 | Effects of auranofin and myochrysine on intestinal transport and morphology in the rat. | 1987 Jul | Auranofin (SKF-D 39162) is an oral gold preparation for the treatment of rheumatoid arthritis. One of its major side effects is diarrhoea. To determine one possible mechanism for this we compared the effects of auranofin and myochrysine on intestinal water and solute transport in the rat. Jejunal perfusion with 2 mM auranofin (n = 5) induced fluid and electrolyte secretion and inhibited glucose absorption (p less than 0.01). Auranofin (0.2 mM) induced fluid secretion in the jejunum (n = 5; p less than 0.01) and colon (n = 6; p less than 0.01). In contrast, 2 mM myochrysine enhanced jejunal water and electrolyte absorption (n = 6; p less than 0.02). Both compounds enhanced absorption of mannitol (p less than 0.01). Perfusion of 0.2 mM auranofin for two hours had no significant effect on mucosal c-AMP levels (n = 4). After perfusion for two hours with 2 mM auranofin the jejunal mucosa showed severe injury by light and scanning electronmicroscopy while myochrysine had no apparent effect. The damage after perfusion with 0.2 mM auranofin for two hours was less severe. Auranofin was more rapidly absorbed than myochrysine (p less than 0.05). These effects provide an explanation for the diarrhoea associated with auranofin therapy. | |
| 3124495 | Biochemistry of hyaluronan. | 1987 | Hyaluronan (hyaluronic acid) is a linear polysaccharide formed from disaccharide units containing N-acetylglucosamine and glucuronic acid. It is ubiquitously distributed in the organism but is found in the highest concentrations in soft connective tissues. The molecular weight of hyaluronan is usually in the order of 10(6) to 10(7). Due to hydrogen bonding, the chain is rather stiff and the molecule behaves in solution as an extended, randomly kinked coil. Molecules of hyaluronan start to entangle already at concentrations of less than 1 g/l and form a continuous polymer network. Some of the functions of the polysaccharide have been connected with the unique physical chemical characteristics of the network such as its rheological properties, flow resistance, osmotic pressure, exclusion properties and filter effect. Hyaluronan is synthesized in the cell membrane by adding monosaccharides to the reducing end of the chain. The precursors are UDP-glucuronic acid and UDP-N-acetylglucosamine. The polysaccharide grows out from the cell surface and it can be shown that fibroblasts, for example, surround themselves with a coat of hyaluronan. The rate of biosynthesis is regulated by various factors, such as growth factors, hormones, inflammatory mediators, etc. The responsible enzyme, hyaluronan synthase, is a phosphoprotein and the regulation of the synthetic rate is apparently via phosphorylation. The hyaluronan is at least partly carried by lymph flow from the tissues. Part of the material is taken up and degraded in the lymph nodes. Another part is carried to the general circulation and taken up in the endothelial cells in the liver sinusoids. These cells have specific receptors for hyaluronan, which also recognize chondroitin sulphate. The uptake in the liver of high-molecular weight hyaluronan is very efficient and its normal half-life in serum is only in the order of 2 to 5 min. The polysaccharide is rapidly degraded in the lysosomes to low-molecular weight products, lactate and acetate. The total turnover of hyaluronan in serum is in the order of 10-100 mg/24 h. The normal concentration of hyaluronan in serum is less than 100 micrograms/l with a mean of 30-40 micrograms/l. High serum levels have been noted in liver cirrhosis (impaired uptake in the liver) and rheumatoid arthritis (increased synthesis in the tissues). Hyaluronan has been shown to interact specifically with certain proteins and cell surfaces. It binds to proteoglycans in cartilage and other tissues and fills an important structural role in the organization of the extra-cellular matrix.(ABSTRACT TRUNCATED AT 400 WORDS) | |
| 1722967 | A double blind, randomised, multicentre comparison of two doses of intravenous iloprost in | 1991 Nov | OBJECTIVE: To compare low (0.5 ng/kg/min) and standard dose (2 ng/kg/min) iloprost (a stable carbacyclin analogue of prostacyclin) in patients with Raynaud's phenomenon secondary to connective tissue disorders. DESIGN: Double blind, random allocation, three six hour infusions on consecutive days. Follow up period eight weeks. SETTING: Rheumatology units, five teaching hospitals. PATIENTS: 55 Patients with Raynaud's phenomenon (greater than seven attacks per week), 32 secondary to well documented classical progressive systemic sclerosis (American Rheumatism Association criteria), 11 CREST syndrome, 5 mixed connective tissue disease, 1 rheumatoid arthritis, 1 Sjögren's syndrome, 1 childhood dermatomyositis, and 4 abnormal nailfold capillaroscopy and antibody profiles but no definite diagnosis. INTERVENTIONS: All other treatment for Raynaud's phenomenon was discontinued two weeks before entry. 28 Patients were randomly allocated to receive the low dose, 27 the standard dose. Differing dilutions allowed infusion rates to be started at 10 ml/h with increments of 10 ml/h every 15 minutes until infusion rates reached 0.5 ng/kg/min and 2 ng/kg/min respectively. MAIN OUTCOME MEASURE(s)--Reduction in frequency, duration, and severity of attacks of Raynaud's phenomenon. Assessment of ulcer and ischaemic lesion healing. RESULTS: Both dosage regimens were equally effective in reducing severity, frequency, and duration of Raynaud's attacks. Ulcer healing occurred to similar degree in both treatment groups (standard dose 44%, low dose 39%). Low dose was associated with significantly fewer side effects. CONCLUSIONS: Both dosage regimens reduce severity of Raynaud's phenomenon and encourage ulcer healing. Low dose was associated with fewer side effects and was better tolerated by the patients. | |
| 1901563 | Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in in | 1991 Mar | Increased small intestinal permeability caused by non-steroidal anti-inflammatory drugs (NSAIDs) is probably a prerequisite for NSAID enteropathy, a source of morbidity in patients with rheumatoid arthritis. This increased small intestinal permeability may be a summation of a local effect during drug absorption, a systemic effect after absorption, and a local effect of the drug excreted in bile, but the relative contribution made by these factors is unknown. We assessed the effect of indomethacin and nabumetone on intestinal permeability. The principal active metabolite of nabumetone, 6-methoxy-2-naphthylacetic acid, is not subject to appreciable enterohepatic recirculation. Twelve volunteers were studied before and after one week's ingestion of indomethacin (150 mg/day) and nabumetone (1 g/day) with a combined absorption/permeability test. Neither drug had a significant effect on the permeation of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose. Indomethacin increased the permeation of radioactive 51chromium ethylenediaminetetra-acetic acid (51Cr EDTA) significantly from baseline (mean (SEM) 0.63 (0.09)% v 1.20 (0.14)%, p less than 0.01) but nabumetone did not (0.70 (0.10)% p greater than 0.1). These results were supported by the 51Cr EDTA/L-rhamnose urine excretion ratios, which reflect changes in intestinal permeability. They suggest that NSAIDs increase intestinal permeability during absorption or after biliary excretion and that the systemic effect is of minor importance. | |
| 2044408 | Immunological dysregulation of lymph nodes in AIDS patients. | 1991 | Changes in immune competent tissues of the HIV-1-infected person reflect to a certain extent the kind and intensity of immunological dysregulations. The diagnostic approach, however, must include immunophenotyping of cells, immunovirological studies of virus distribution in diseased tissues, and functional tests in addition to classical morphology. The latter technique alone just serves as a crude screening method since structural lesions in lymphoid tissues do not permit discrimination from other HIV-independent immune deficiency and autoimmune disorders. Although the overall appearance of lymph nodes in HIV infection and in chronic autoimmune disorders, such as collagen vascular diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus), is similar, immunophenotyping shows a progressive loss of CD4 cells in HIV infection yet a quantitative increase in this cell population in autoimmune disorders (Krueger 1985a). In addition, there are other persistent active infections by lymphotropic viruses (e.g., EBV or HHV-6) which can cause structural and cellular changes in lymphoid tissues closely resembling HIV-induced lesions (Krueger et al. 1988b; Krueger 1985b). The pathological diagnosis therefore nedds to be supplemented by serological studies and--in selected cases--by in situ hybridization for the demonstration of viral genome. Southern blotting for viral DNA can only detect high numbers of viral genome copies in tissue extracts, not in which cell population the virus resides (e.g., malignant cells vs associated "normal" cells), while the polymerase chain amplification reaction, the most sensitive of all (Buchbinder et al. 1988), cannot yet differentiate between latent and (disease-related) active infection. Taking into consideration the above-described precautions in the evaluation of lymphatic lesions, there are a number of characteristic changes which reflect well the sequelae of HIV infection itself and of the ensuing immune dysregulation. Progressive loss of CD4 cells in the paracortex of lymph nodes and in the peripheral blood leads to inversion of the CD4/CD8 ratio. Loss of demonstrable CD4 cells is probably the consequence not only of cell lysis by HIV-1 infection (note: discrepancy between HIV-1 genome positive cell numbers and depletion of CD4 cells) but also of decreased CD4 marker synthesis in infected cells (Stevenson et al. 1987). In this context it is interesting that Fouchard et al. (1986) were able to show HIV expression in CD8 cells and theorized that these developed from infected CD4 cells which subsequently lost the CD4 epitope and expressed CD8.(ABSTRACT TRUNCATED AT 400 WORDS) | |
| 2230125 | Monosodium urate crystals stimulate phospholipase A2 enzyme activities and the synthesis o | 1990 Nov 15 | Eicosanoids are important mediators of the inflammatory response to monosodium urate crystals (MSUC) that results in gout. Phospholipase enzymes cleave fatty acids from membrane phospholipids, and this is thought to be the rate-limiting step in eicosanoid production. To understand better the mechanism of eicosanoid production in this disease, we stimulated human peripheral blood neutrophils and monocytes with MSUC and measured phospholipase enzyme activities. MSUC stimulated both intracellular and secretory phospholipase A2 enzyme activities in a time and concentration-dependent manner. Specificity was observed, as phospholipase C activities were not affected. Pretreatment with colchicine, but not aspirin, indomethacin, allopurinol, or islet activating protein, abrogated the enhanced phospholipase A2 activities. We have recently isolated and characterized a phospholipase A2 activating protein termed PLAP from synovial fluid from patients with rheumatoid arthritis, and from murine and bovine cell lines. PLAP was detected in gouty synovial fluid by immunodot blotting and ELISA assays and expressed the same characteristics as PLAP identified from other sources. To examine the role of PLAP in MSUC-induced phospholipase A2 stimulation, we treated cells with MSUC and observed an increase in immunoreactive PLAP. This response also could be blunted by colchicine, but not other drugs. Both phospholipase A2 and PLAP induced production by human monocytes of PGE2 and leukotriene B4 by neutrophils. These findings suggest that phospholipase A2 activation in response to MSUC requires an intact microtubule structure, and that phospholipase A2 and PLAP may be important modulators of at least a portion of the gouty inflammatory response. | |
| 2364605 | The influence of continuous passive motion on outcome in total knee arthroplasty. | 1990 Jul | All primary condylar total knee replacement arthroplasties (TKAs) performed from 1977 to 1984 at the authors' institution were divided into two groups based on the use of continuous passive motion (CPM) in the immediate postoperative period. The control group consisted of 73 patients who were treated with 95 TKAs without postoperative CPM. The average age was 65.4 years. The study group consisted of 38 patients who had 51 TKAs in which CPM was used postoperatively. The mean patient age was 62.8 years. The most common diagnoses in both groups were osteoarthritis and rheumatoid arthritis. Range of motion (ROM) was recorded preoperatively, at discharge, at three months, one year, two years, and at the last follow-up visit. There were no statistically significant differences in the ROM between the two groups at any of these time periods. At two years, the mean flexion and extension in the study group were 99 degrees and -4 degrees, respectively, compared to 103 degrees and -5 degrees in the control group. The average hospital stay was 11.2 days in the study group, whereas it was 15.1 days in control group. In the control group, there was one superficial infection, no deep infections, and four pulmonary emboli compared with three superficial infections, two deep infections, and no pulmonary emboli in the study group. There was no difference in the transfusion requirements between the two groups. CPM is advocated by the authors to help achieve discharge ROM earlier, but the protocol has been changed to begin CPM on the second postoperative day to allow the wound to stabilize. | |
| 2192535 | Noninvasive methods to study autonomic nervous control of circulation. | 1990 | The major findings and conclusions of this study are the following: 1. Indirect evidence suggested that nervous afferentation from the cutaneous thermoreceptors and nervous efferentation to the skin blood vessels mediated the 0.01-0.10 Hz thermally entrained response of the oscillations of the forearm skin blood flow in supine and upright subjects. 2. Postural stimulation decreased skin blood flow and oscillations of skin blood flow. The 0.10 Hz thermal stimulation interacted with the postural stimulation by increasing the oscillations of skin blood flow from sitting to standing position on the contrary to the expected postural effect. 3. The thermal entrainment of periodic heart rate variability was not constant. Both 0.01-0.10 Hz thermal and postural and sensory stimulations affected the periodic heart rate variability selectively at the frequency of the periodic stimulus or the less than 0.12 Hz frequencies. 4. The periodic thermal stimulation had a frequency-selective effect on the oscillations of the neonatal heart rate. The thermally stimulated reactivity increased with an increased maturity of a neonate. 5. Intermittent tilting had a frequency-selective influence on the oscillations of heart rate. Continuous deep breathing entrained the periodic heart rate variability. The estimation of the power spectral density function of heart rate quantified the chronotropic respiratory effects more accurately than the statistical indices of heart rate variability. 6. Response of periodic heart rate variability to intermittent tilting and deep breathing stimulation suggested normal vagal control of heart rate in children with juvenile diabetes and juvenile rheumatoid arthritis. 7. Normal vagal bradycardic response was found during the phase IV of the Valsalva manoeuvre in functionally abnormal nervous control of circulation. The simulated diving test was not found clinically useful. 8. The ratio of electrical to electromechanical systole of the heart was greater than 1.00 both at rest and during the orthostatic, Valsalva and diving reflex tests. This finding suggested constantly exaggerated sympathetic cardiac inotropic control during vagal and sympathetic stimulation of heart rate. 9. The decreased thermally stimulated heart rate variability was interpreted as an indication of inhibited vagal modulation of the sinoatrial node of the heart in subjects with dystonic symptoms and orthostatic intolerance. The exaggerated sympathetic reactivity of these subjects explained the abnormally high gain of periodic heart rate variability to 0.01-0.03 Hz periodic thermal stimulation. | |
| 2141033 | The effect of dual inhibitor, SK&F 86002, on helper T cell functions. | 1990 | SK&F 86002, a mixed cyclooxygenase-lipoxygenase inhibitor, was examined for its effects on helper T cell functions. The drug was found to inhibit concanavalin A-induced mitogenesis of splenic T cells (IC50 = 13 microns), the mixed lymphocyte response (IC50 = 16 microM), and proliferation of antigen specific T cells (cloned line, IC50 = 11 microM; uncloned line, IC50 = 13 microM). In contrast, another mixed cycloxygenase-lipoxygenase inhibitor, BW775c, did not have such effects at non-cytotoxic levels. These T cell functions are believed to be dependent on the effects of elaborated IL-1. SK&F 86002 has been shown to inhibit the production of mature IL-1 (IC50 = 1 microM), possibly accounting for the anti-inflammatory effects of the drug in rheumatoid arthritis models. In an in vivo model of contact sensitivity, SK&F 86002 was able to inhibit mouse footpad swelling, demonstrating additional anti-inflammatory activity. As an inhibitor of IL-1 synthesis or release, SK&F 86002 may be useful for the treatment of T cell-dependent inflammation. | |
| 3126818 | Blood coagulation and bone metabolism: some characteristics of the bone resorptive effect | 1988 Mar 17 | Chronic inflammatory processes are often associated with bone resorption. Stimulated by the current great interest in the role of coagulation factors in inflammation and immune injury, we have studied the effect of thrombin on mouse calvarial bones in vitro. Thrombin caused a dose-dependent (0.1-7 U/ml) stimulation of 45Ca release from neonatal mouse calvarial bones. Thrombin also stimulated the mobilization of stable calcium and inorganic phosphate, the release of 3H from [3H]proline-labelled calvaria, the production of lactate and the release of the lysosomal enzymes, beta-glucuronidase and beta-N-acetylglucosaminidase. Thrombin also enhanced 45Ca release from fetal rat long bones, although this bone resorption assay was less sensitive to thrombin than the mouse calvarial system. The bone resorption stimulatory activity of thrombin in mouse calvaria could be inhibited by calcitonin and an increased concentration of phosphate in the culture medium. Thrombin-induced 45Ca release in mouse calvaria was sensitive to inhibition by hydrocortisone and dexamethasone. By contrast, 45Ca release response to parathyroid hormone was insensitive to corticosteroids. The prostaglandin synthetase inhibitors indomethacin, meclofenamic acid and naproxen and 5,8,11,14-eicosatetraynoic acid reduced 45Ca release from thrombin-stimulated calvaria. However, significant stimulation by thrombin could be achieved also in bones treated with inhibitors of arachidonate metabolism. The results obtained suggest that thrombin can stimulate cell-mediated bone resorption by an osteoclast-dependent mechanism. The mechanism of action may involve both prostaglandin-dependent and prostaglandin-independent pathways. Our findings indicate that thrombin may contribute to the bone resorptive processes seen in periodontal disease and rheumatoid arthritis. | |
| 3327814 | The genetic origin of murine lupus-associated autoantibodies. | 1987 Dec | Systemic lupus erythematosus and rheumatoid arthritis in human and murine systems are characterized by circulating autoantibodies and immune complex deposition in various organs causing tissue damage and disease. To define the molecular and clonotypic origin of these anti-self responses, and to determine whether abnormalities in Ig genes or somatic mechanisms generating autoantibody diversity may contribute to lupus etiology, we performed molecular analyses of the Ig germline gene organization and the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice. Comparative restriction fragment length polymorphism analysis of a large number of Ig gene loci from autoimmune and normal mice indicated that (a) lupus can develop in different Ig heavy and kappa light chain variable region gene haplotypes, and (b) the Ig germline genes in lupus mice might be normal. To determine whether autoantibodies are encoded by unique Ig gene segments present in the normal germline repertoire, but not expressed in exogenous responses, we compared nucleic acid sequences encoding lupus autoantibodies and antibodies against foreign antigens. Similar, and in some instances even identical, gene segments were expressed in both types of antibodies, indicating that anti-self and anti-foreign responses use the same, or at least an overlapping, germline gene repertoire. A large variety of Ig variable, diversity, and joining gene segments encoded these autoantibodies with different specificities. Hence, the overall murine lupus-associated anti-self response may be essentially unrestricted. Furthermore, limited evidence has been obtained that both germline genes and somatically mutated genes encode autospecificity, making gross abnormalities in mechanisms for somatic mutation of Ig variable genes unlikely.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 3319347 | Clinical pharmacokinetics of D-penicillamine. | 1987 Nov | Penicillamine exists as 2 stereoisomers, but only the D-isomer is used therapeutically. Its chemical reactivity derives from its functional groups, of which the thiol group seems the most important. It is difficult to determine penicillamine in biological fluids because of its instability, the presence of endogenous compounds with a thiol function, and the various chemical forms in which it occurs, namely reduced free penicillamine, penicillamine bound to proteins, and internal (P-S-S-P) and mixed (P-S-S-C) disulphides. The earliest assay methods (colourimetry, isotopic methods, gas-phase chromatography) were neither sensitive nor specific. High performance liquid chromatography with electrochemical detection has led to a more specific assay for D-penicillamine, with detection based on either derivatisation reactions or on electro-oxidisation of the thiol function. With dual-electrode detectors (Au/Hg) disulphides can be assayed directly. D-penicillamine is absorbed rapidly but incompletely (40 to 70%) in the intestine, with wide interindividual variations. Food, antacids and, in particular, iron reduce absorption of the drug. Its bioavailability is also dramatically decreased in patients with malabsorption states. The peak plasma concentration occurs at 1 to 3 hours after ingestion, regardless of dose, and is of the order of 1 to 2 mg/L after an oral dose of 250 mg; some investigators have reported a double peak in plasma, which is probably not due to an enterohepatic cycle. The concentration in plasma then decreases rapidly, generally following a biphasic curve. When long term treatment is discontinued, there is a slow elimination phase lasting 4 to 6 days, which suggests that there is a 'deep compartment' or 'slow pool of the drug reversibly bound to tissues', particularly the skin. This may explain the persistence of its therapeutic effect and the occurrence of undesirable side effects after treatment has been stopped. During long term treatment plasma concentrations are highly variable between individuals. They do not seem to be correlated with the activity or the toxicity of D-penicillamine in patients with rheumatoid arthritis. More than 80% of plasma D-penicillamine is bound to proteins, particularly albumin. The rest is mainly in the free reduced form or as disulphides. Only a small portion of the dose is metabolised in the liver to S-methyl-D-penicillamine. The route of elimination is mainly renal; disulphides represent the main compounds found in the urine. Faecal excretion corresponds mainly to the non-absorbed fraction of the drug. | |
| 3549473 | Randomised study of the influence of non-steroidal anti-inflammatory drugs on the treatmen | 1987 Feb | Sixty-seven patients with rheumatic disease, treated with non-steroidal anti-inflammatory drugs (NSAIDs), entered a controlled trial with a diagnosis of duodenal (n = 51), gastric (n = 14), or gastric and duodenal (n = 2) ulcers. The main objectives of the study were a comparison of ranitidine and sucralfate in ulcer treatment, and to observe the influence of continued NSAID administration during peptic ulcer therapy. Ulcers healed within nine weeks in 52 patients. The mean healing time was similar in 27 patients given ranitidine 150 mg bd (4.9 weeks) and 25 patients given sucralfate 1 g qid (4.6 weeks). In patients with unhealed ulcers after nine weeks of treatment, healing was obtained in seven after further therapy for 3-9 weeks. Of the 30 patients who continued NSAIDs during treatment with either ranitidine or sucralfate, 23 ulcers healed (mean healing time: 5.0 weeks). Of 32 patients in whom NSAIDs were stopped, ulcer healing was documented in 29 (mean healing time: 4.6 weeks). The difference in healing rates was not statistically significant (p greater than 0.10). The outcome of ulcer treatment did not differ in patients with rheumatoid arthritis and patients suffering from osteoarthritis. During a 12 month follow up 14 symptomatic ulcer recurrences were recorded. | |
| 3794343 | An enzyme-linked immunoabsorbent assay for the quantitation of the terminal complement com | 1986 Dec 24 | A sensitive and simple enzyme-linked immunoabsorbent assay (ELISA) has been developed to measure the terminal complement complex (TCC) in solution. Commercially available antibodies to the native complement (C) components C5 and C9 were used in a double antibody sandwich technique sensitive enough to detect 0.3 microgram/ml of purified TCC. The TCC was not detected in normal human serum (NHS) nor was it generated when sera from patients with a genetic deficiency of functional C5, C7, C8 beta or C9 were activated with cobra venom factor (CVF). If the C8 beta deficient serum was reconstituted with the C8 beta chain and incubated with CVF, TCC were formed and detected by the assay. In in vitro experiments, the TCC was detected in NHS activated by either the classical or alternative pathway even when there was no measurable consumption of C5, C8 or C9. In addition, adaptation of a detergent extraction procedure permitted the quantitation by the assay, of TCC which were generated on sensitized sheep erythrocyte membranes. Experiments to test sample handling conditions showed no generation of TCC in NHS after four freeze/thaw cycles and spontaneous formation only if NHS had been incubated at 37 degrees C for 48 h. The TCC in zymosan-activated NHS were stable at 37 degrees C for 1 week. Patients with C activation associated diseases such as SLE and rheumatoid arthritis had increased levels of TCC that correlated with positive clinical tests for inflammation, even though C levels were normal when measured by routine techniques. These results suggest that this ELISA will provide a valuable tool for studying the role of C in the pathogenesis of C-mediated diseases and in examining the mechanism of tissue injury in in vitro experimental systems. | |
| 3019354 | Differential effects of mepacrine, chloroquine and hydroxychloroquine on superoxide anion | 1986 Sep 15 | The 4-aminoquinolines chloroquine (CQ) and hydroxychloroquine (HCQ), and previously the 9-aminoacridine mepacrine (quinacrine) (MP), have been widely used in the treatment of inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus. Their effects are believed to be mediated through phagocytic cells but the precise biochemical basis remains uncertain. We have investigated the effects of these drugs on monocyte superoxide anion (SO) generation elicited by 5 different stimuli-opsonised zymosan (STZ), FMLP, A23187, TPA and fluoride--and sought correlations with effects on two processes which have been linked with monocyte activation, namely arachidonate (AA) release and transmethylation of phosphatidyl ethanolamine (PE) to phosphatidylcholine (PC). In all experiments conditions were adjusted to achieve leucocyte concentrations of drug comparable to those found during in vivo therapy. Neither CQ nor HCQ had any marked effect on SO release induced by TPA, A23187 or fluoride ion, excluding a significant effect on protein kinase C (PKC), calmodulin-dependent kinase(s) or the membrane-bound, superoxide generating NADP(H) oxidase. In contrast MP inhibited the response to TPA and A23187. Each drug also had different effects on surface receptor-dependent responses; thus HCQ inhibited FMLP- but not STZ-induced SO release, whereas CQ and MP inhibited the response to both stimuli. Each drug also displayed different effects on AA release and phospholipid (PL)-methylation; MP and HCQ, but not CQ, inhibited STZ-stimulated AA release while MP and CQ but not HCQ inhibited basal rates of PL-methylation in mononuclear cells (MNC). However, only MP inhibited PL-methylation in an enriched monocyte population. We conclude that despite their close structural similarity, MP, CQ and HCQ each have different metabolic effects and their actions cannot simply be attributed to inhibition of lysosomal functions. Other possible mechanisms of action are discussed. The selective effects of each drug also provide further evidence for multiple pathways of monocyte activation. |