Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
10947304 The cost effectiveness of misoprostol prophylaxis alongside long-term nonsteroidal anti-in 2000 Mar OBJECTIVE: This study considered the cost effectiveness of misoprostol prophylaxis for nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal damage, using data from the Misoprostol Ulcer Complications Outcomes Safety Assessment (MUCOSA) trial. The initial aim was to gain listing of misoprostol on the Australian National Formulary. DESIGN: The economic evaluation followed a 2-stage approach in considering the cost effectiveness of misoprostol, a 'within-trial' analysis followed by a simple modelled analysis which explored the implications of the trial results for life-years saved beyond the trial setting. The perspective of the evaluation is that of the healthcare system. SETTING: Three different populations were considered: the total trial population; patients with a history of peptic ulcer disease; and patients over 65 years of age. STUDY POPULATION: Patient data were taken from the MUCOSA trial, which involved 8843 patients receiving continuous NSAID therapy for the control of rheumatoid arthritis. INTERVENTIONS: Misoprostol plus any NSAID therapy was compared with placebo (no misoprostol) plus any NSAID therapy. MAIN OUTCOME MEASURES AND RESULTS: The study found the incremental cost per definite serious gastrointestinal complication avoided with misoprostol was 39,603 Australian dollars ($A) for the total trial population, $A5599 for patients with a history of peptic ulcer disease and $A35,405 for patients over 65 years of age. The incremental cost per life-year saved with misoprostol was $A41,866 for the whole group, $A6244 for patients with a history of peptic ulcer disease and $A40,322 for patients over 65 years of age. CONCLUSIONS: The study found misoprostol to be cost effective in this setting.
10841070 [Properties and features of nabumetone]. 2000 Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) of the 2,6-disubstituted naphthylalkanone class. It is a prodrug metabolised to an active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), which preferentially inhibits cyclo-oxygenase-2 (COX-2) and has both anti-inflammatory and analgesic properties. The efficacy of nabumetone is comparable to that of other NSAIDs currently marketed in France for the treatment of rheumatoid arthritis and osteoarthritis. Nabumetone is metabolised to 6-MNA by extensive first-pass metabolism. This active metabolite is subsequently conjugated and excreted in urine. 6-MNA does not undergo enterohepatic recirculation, which may have implications for comparative gastrointestinal toxicity. Substantial concentrations of 6-MNA are achieved and maintained in synovial fluid, which is close to the proposed site of action in chronic arthropathies. The long plasma half-life of 6-MNA (20 to 24 hours) and its persistence in synovial fluid facilitate a once-daily dosage regimen. Nabumetone compares favourably with other NSAIDs with respect to its renal and gastrointestinal adverse effect profile, although increased clinical vigilance of drug-related adverse events relating to these organ systems is still recommended. In addition, in vitro experiments have shown this drug to have a good cartilage tolerability profile. Whether nabumetone has clinical utility in cardiovascular disorders remains to be determined. The unique pharmacokinetic and pharmacodynamic properties of nabumetone make it a welcome addition to the growing arsenal of drugs used in the treatment of chronic arthropathies. There may be clinical advantages in terms of the relative tolerability profile of nabumetone, given that this drug has a low COX-2/COX-1 ratio compared with other nonselective NSAIDs.
10825705 Motor cortical dysfunction disclosed by single and double magnetic stimulation in patients 2000 Jun OBJECTIVE: To investigate the motor cortex by single and double magnetic stimulation, in patients with fibromyalgia. METHODS: Thirteen patients with fibromyalgia and 13 age-matched healthy subjects were examined. We evaluated, in both limbs, motor evoked potential (MEP) latency and amplitude and the MCA/MPA ratio, i.e. MEP cortical amplitude (MCA) /maximal peripheral amplitude of the M response (MPA), the central conduction time (TCC) and the length of the silent period (SP). With double magnetic stimulation, different time intervals between shocks were used: with delays between shocks of 4, 25, 55 and 85 ms, the intensities of the conditioning shock were 80% the relaxed threshold. With delays between shocks of 55, 85, 100, 155, 200, 255 and 355 ms, the intensities of the conditioning shocks were set at 150% the relaxed threshold. In all cases, the intensity of the test shock was 150% the relaxed threshold. The results were also compared with those obtained in 5 women affected by rheumatoid arthritis (RA). RESULTS: As compared to control, the cortical relaxed threshold was enhanced on both sides and limbs (P<0.05). The cortical silent period recorded with single magnetic stimulation was reduced in the upper limbs (P = 2.7x10(-11)) and lower limbs (both sides P = 3.6x10(-5)). The other parameters investigated were normal. With double magnetic stimulation, facilitatory phenomena were absent in fibromyalgic patients and the inhibitory responses recorded with a delay of 155 ms were reduced (P = 0.0052). No significant differences were noted between FM and RA patients. CONCLUSION: This study demonstrated motor cortical dysfunction in patients with fibromyalgia involving excitatory and inhibitory mechanisms. This indicates motor cortical involvement and supports the hypothesis of aberrant central pain mechanisms. The absence of differences between FM and RA suggest that the lesions were not specific and could be related to chronic pain disorders within the central nervous system.
10791647 Longitudinal split of peroneus brevis tendon. A report on two cases. 2000 BACKGROUND AND AIMS: To describe the clinical findings and surgical treatment of peroneus brevis split. MATERIAL AND METHODS: Two cases of longitudinal split of the peroneus brevis tendon are reported. One of the patients was a healthy middle-aged woman, who had fallen out of a car in a traffic accident and sprained her right ankle. Lateral ankle sprain was diagnosed and treated with a compression bandage. Lateral ankle pain persisted, however, with some swelling in the peroneal tendon region. MRI revealed a longitudinal partial rupture of the peroneus brevis tendon, which was treated surgically 12 months after the trauma. The second case was a 53-year-old woman, who had been suffering from rheumatoid arthritis for 2 years. Chronic pain and swelling in the peroneal tendon region were treated with 6 local corticosteroid injections without significant relief. Preoperative ultrasonography showed effusion of the peroneal tenosynovium, but the operation revealed a longitudinal split in the peroneus brevis tendon. RESULTS: In the first case, a single central peroneus brevis split was repaired with side-to-side suturation. After four weeks with a below-knee cast the patient was allowed to walk freely. At follow-up 12 months postoperatively, she was satisfied, although she still had some exertion pain in her ankle. In the second case, the torn fragment of the peroneus brevis tendon was excised and the ankle was mobilized early. Healing was complicated by a wound fistula, which was treated with antibiotics. Subluxation of the peroneus longus tendon necessitated a reoperation, which revealed a rerupture and a defect of the peroneus brevis tendon. The subluxation was repaired and the ruptured tendon ends were revised, followed by four weeks of below-knee cast immobilization, after which the patient was allowed to walk freely. The outcome was good. CONCLUSION: Peroneus brevis split easily goes unrecognised or misdiagnosed. It must be considered in patients with a history of single or recurrent ankle sprain or a chronic inflammatory disease. Lateral ankle pain, diffuse or local swelling in the peroneal tendon region, and a stable or instable ankle with no peroneal weakness are the main symptoms and findings. MRI is the most exact method for diagnosing tendon split. Surgical treatment usually gives good results.
10716453 The role of tumor necrosis factor in the pathophysiology of heart failure. 2000 Mar 1 Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors and cachexia, it is now recognized that TNF participates in the pathophysiology of a group of inflammatory diseases including rheumatoid arthritis and Crohn's disease. The normal heart does not express TNF; however, the failing heart produces robust quantities. Furthermore, there is a direct relationship between the level of TNF expression and the severity of disease. In addition, both in vivo and in vitro studies demonstrate that TNF effects cellular and biochemical changes that mirror those seen in patients with congestive heart failure. Furthermore, in animal models, the development of the heart failure phenotype can be abrogated at least in part by anticytokine therapy. Based on information from experimental studies, investigators are now evaluating the clinical efficacy of novel anticytokine and anti-TNF strategies in patients with heart failure; one such strategy is the use of a recombinantly produced chimeric TNF alpha soluble receptor. Thus, in view of the emerging importance of proinflammatory cytokines in the pathogenesis of heart disease, we review the biology of TNF, its role in inflammatory diseases, the effects of TNF on the physiology of the heart and the development of clinical strategies that target the cytokine pathways.
10408069 [In vitro transduction of human osteoblast cell populations with retroviral vectors]. 1999 Apr OBJECTIVES: The involvement of cytokines in degeneration and inflammation of human tissue is well established. Interleukin-1 (IL-1) is a major agent in the pathophysiology of periarticular bone resorption in rheumatoid arthritis and in osteoporosis. Because the use of recombinant cytokines and growth factors is limited due to their short half lives, techniques are needed to get a permanent release of these therapeutic proteins. The rational of this study was to show that retroviral transduction of human osteoblastic cells is possible in vitro using the marker gene LacZ and the potentially therapeutic gene encoding for human interleukin-1 receptor antagonist protein (IL-1Ra). Different transduction techniques were combined to improve the rate of transduction in vitro. METHODS: Osteoblastic cells were isolated from human spongious bone and cultured in vitro. The beta-galactosidase (LacZ) gene and the cDNA of IL-1Ra were introduced into the isolated cells by retrovirus mediated gene transfer. LacZ activity was determined by Xgal staining, IL-1Ra was measured quantitatively by ELISA. RESULTS: The transfer of retroviral IL-1Ra led to IL-1Ra expression of 8614 to 10,089 pg IRAP/50,000 cells/48 h. By combining different techniques to improve transduction, the X-gal staining established a rate of transduction of 60%. CONCLUSION: Our results demonstrate that retroviral transduction of human osteobalstic cells is possible in vitro, and leads to high levels of the synthesized transgene product. The rate of retroviral transduction can be accelerated in vitro.
10368731 [Cold tap water as a source of fatal nosocomial pneumonia due to Legionella pneumophila in 1999 May 15 OBJECTIVE: Report of the technical, microbiological and epidemiological investigation following 2 cases of fatal Legionella pneumonia. DESIGN: Descriptive. METHOD: Faced with 2 nosocomial cases in a rehabilitation centre in the South of Limburg, the Netherlands, the water supply was investigated. Water temperatures from different taps were measured. Legionella cultures were made from respiratory patients' specimens, water samples and smears from all mixing taps (used in showers), samples from hot and cold water taps from the infected ward and from the five other wards. The strains were typed by serotyping and polymerase chain reaction. RESULTS: The circulating cold water sometimes warmed up to 40 degrees C (within the Legionella growth range). From the sputum of the 2 male patients with rheumatoid arthritis who died of Legionella pneumonia the same Legionella pneumophila (serotype I) was cultured as from the water supply. Of the showers on the contaminated ward 19% (12/63) were positive for Legionella as were 59% (35/59) of the cold water taps. Cultures from the hot water supply were negative just like control cultures from five other wards and swabs from showerheads and hoses. The cold water tubes ran next to the hot water tubes and the central heating system in the same shaft. On the infected ward patients were absent during the weekends. As one of the subsequent measures, the cold water pipes were relocated to another shaft. CONCLUSION: The combination of an elevated cold water temperature caused by heating along a distance by nearby hot water and heating piping and the regular stasis of water during the weekends when the ward was closed, most probably stimulated the multiplication of Legionella in the water supply. In order to minimize contamination of cold water its temperature must be kept below 20 degrees C. Surveillance of intramural water systems is necessary to prevent nosocomial infections.
10349205 [Pulmonary mucosa-associated lymphoid tissue lymphoma in a patient with myasthenia gravis] 1998 Oct Mucosa-associated lymphoid tissue lymphomas are a subgroup of non-Hodgkin's lymphoma. The lung is the most frequent non-gastrointestinal organ they affect. Pulmonary mucosa-associated lymphoid tissue lymphoma usually appears as a solitary mass often accidentally discovered on chest radiography. Diffuse, bilateral involvement is rare. The association of mucosa-associated lymphoid tissue lymphoma with autoimmune diseases has been reported, and a pathogenetic role has been suggested for the autoimmune process in its development. Optimum management has not yet been standardized. The case described here is a mucosa-associated lymphoid tissue lymphoma with multiple, unusually large opacities involving both lungs. The patient, a 55-year-old woman, also suffered from myasthenia gravis, an autoimmune disease characterized by an autoaggressive process against the acetylcholine receptors. Whereas other autoimmune diseases such as rheumatoid arthritis, polymyositis, and fibrosing alveolitis have been correlated with mucosa-associated lymphoid tissue lymphoma, an association between this lymphoma and myasthenia gravis has not yet been reported. Complete resolution of the pulmonary opacities was obtained with cyclophosphamide treatment. It continues at 15 months after the suspension of therapy.
10072544 Selective regulation of cytokine induction by adenoviral gene transfer of IkappaBalpha int 1999 Mar 1 Macrophages are the major cytokine producers in chronic inflammatory diseases, but the biochemical pathways regulating cytokine production are poorly understood. This is because genetic tools to dissect signaling pathways cannot be used in macrophages because of difficulties in transfection. We have developed an adenoviral technique to achieve high efficiency gene delivery into macrophages and recently showed that spontaneous TNF-alpha production in rheumatoid arthritis joint cells, chiefly from macrophages, is 75% blocked by adenoviral transfer of IkappaBalpha. In this report we use the same adenovirus to investigate whether the production of a number of proinflammatory cytokines (e.g., TNF-alpha, IL-1beta, IL-6, and IL-8) from human macrophages depends on NF-kappaB. While the cytokine response to certain inducers, such as LPS, PMA, and UV light, is blocked by overexpression of IkappaBalpha, the response to zymosan is not. In contrast, anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist) induced by LPS are only marginally inhibited by IkappaBalpha excess. These studies demonstrate several new points about macrophage cytokine production. First, there is heterogeneity of mechanisms regulating both the proinflammatory and anti-inflammatory cytokines within populations of a single cell type. In addition, the results confirm the utility of the adenoviral technique for functional analysis of cytokine induction. The results also confirm that there are autocrine and paracrine interactions regulating cytokine synthesis within a single cell type. The selectivity of NF-kappaB blockade for proinflammatory but not anti-inflammatory mediators indicates that in macrophages, NF-kappaB may be a good target for the treatment of chronic inflammatory diseases.
9973515 Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in who 1999 Feb 15 R6.5 (BIRR-1, Enlimomab), a murine IgG2a mAb to the human ICAM-1, inhibits leukocyte adhesion to the vascular endothelium, thereby decreasing leukocyte extravasation and inflammatory tissue injury. In initial clinical trials, R6.5 proved to be beneficial in reducing both disease activity in refractory rheumatoid arthritis and the incidence of acute rejection after kidney and liver allograft transplantations. However, adverse effects such as fever, leukopenia, or cutaneous reactions were not infrequent. We studied the effects of R6.5 on neutrophil function in whole blood samples ex vivo. Surprisingly, at the concentrations achieved in clinical trials, R6. 5 activated neutrophilic granulocytes, as indicated by a significant increase in expression of the adhesion molecule beta2-integrin CD11b, a concurrent decrease in L-selectin expression, and an enhancement of the oxidative burst activity. Neutrophil activation was not exerted by an anti-ICAM-1 mAb of the IgG1 isotype, by isotype-matched, irrelevant anti-2-phenyloxazolone mAb, or by F(ab')2 fragments of R6.5. Neutrophil activation was completely inhibited by soluble complement receptor type 1. We conclude that in whole blood, R6.5 activates resting neutrophils in a complement-dependent manner. This finding can explain, at least in part, the side effects associated with R6.5 therapy.
9819125 Immunodetection and characterisation of soluble CD105-TGFbeta complexes. 1998 Sep 1 CD105 (endoglin) is a receptor for transforming growth factor beta (TGFbeta). Although methods to measure soluble forms of TGFbeta and CD105 have been published, no assay is available to quantify the receptor-ligand complexes. We describe both an indirect enzyme-linked immunosorbent assay for the quantitation of soluble CD105-TGFbeta1 and the characterization of the complexes by immunoprecipitation and immunoblotting. Mab E9, specifically reactive with CD105, was utilised as the capture reagent in the ELISA system. Detection of complexes was achieved using chicken antibody against TGFbeta1 and the subsequent detection of bound antibody demonstrated by the addition of anti-species antiserum conjugated to horseradish peroxidase (HRP). By using enhanced chemiluminescence and optimised antibodies, the assay was made sufficiently sensitive and reproducible to detect low levels of circulating complexes. Whether the assay had any practical applications was evaluated in breast cancer patients. Plasma levels of CD105-TGFbeta1 were significantly elevated in 59 patients with breast cancer compared to 52 age matched normal women (p < 0.001). Immunoprecipitation using a rabbit anti-CD105 antibody, which reacts with both dimeric and monomeric CD105, and immunoblotting showed that three molecular forms of CD105-TGFbeta1 complexes > 200, 195, and 125 kDa existed in the plasma. We believe these represent the oligomer, dimer and probably the protease degraded form of CD105 complexed to TGFbeta1. The resistance to hypertonic solution, SDS and heat treatment suggested that the soluble CD105-TGFbeta1 complex may be linked by covalent bonds. The measurement of CD105-TGFbeta complexes in the circulation may have important clinical applications not only in cancer but also in patients with other angiogenic diseases such as rheumatoid arthritis, myocardial infarction and stroke.
9797568 Effects of methotrexate on normal articular cartilage in vitro and in vivo. 1998 Jul OBJECTIVE: Methotrexate (MTX) has become the disease modifying drug of choice for the treatment of rheumatoid arthritis (RA). Direct effects of MTX on articular cartilage in vivo and in vitro were studied to determine possible adverse effects of the drug. METHODS: For in vitro experiments, adult bovine articular cartilage explants were cultured in the presence of MTX (0 to 100 microM), and effects on DNA and matrix metabolism were studied. For in vivo studies, 48 adult female rabbits were treated with MTX (30 mg/kg/week intramuscularly) or placebo, respectively, for up to 12 weeks, and effects on the cartilage of the femoral condyles were assessed. RESULTS: In vitro, MTX dose dependently increased the uptake of [3H]-thymidine, and decreased incorporation of [3H]-d-uridine into chondrocytes with a half maximal effect at 0.03 microM, suggesting inhibition of thymidylate-synthetase activity by the drug. MTX also dose dependently reduced the proportion of chondrocytes in S-phase, as determined by flow cytometry. MTX did not affect LDH release from chondrocytes or the proportion of viable cells, nor did it change the rate of protein synthesis, proteoglycan synthesis, proteoglycan breakdown, or the hydrodynamic size of newly synthesised proteoglycans. In vivo, MTX did not appreciably affect proteoglycan synthesis of the chondrocytes, proteoglycan content of the cartilage matrix, density of the chondrocyte population, or histological integrity of the cartilage. CONCLUSIONS: The data suggest the absence of major adverse effects by MTX on articular cartilage proteoglycan metabolism. Chondrocyte DNA metabolism seems to be changed by MTX only in concentrations and exposition periods clearly exceeding those found in synovial fluid of RA patients receiving the commonly prescribed doses of the drug.
9587234 [Subtalar arthrodesis--minimal resection technique]. 1998 INTRODUCTION: This is a prospective clinical and radiological study of the treatment of talocalcaneal deformity or degeneration by a modified technique of isolated talocalcaneal fusion. METHODS: Thirty-six patients were evaluated with clinical examination, plain dorso-plantar and oblique x-rays and CT-scan or magnetic resonance imaging in a follow-up of 32.5 months (range: 20-62). In 12 cases a posterior tibial tendon rupture with secondary osteoarthritis and in 24 cases a posttraumatic secondary osteoarthritis (18 calcaneal fractures, 3 talar fractures, 2 axial traumas with secondary talar necrosis and 1 rheumatoid arthritis with calcanear and talar fracture) were the indications for arthodesis. RESULTS: On a visual analog pain scale the patients graded their pain preoperatively at 4.4 and postoperatively at 1.1. The subjective results showed in 12 cases (33.3%) complete satisfaction, in 10 cases (27.7%) satisfaction with minor reservation, in 11 cases (30.5%) satisfaction with major reservation and in 3 cases (8.5%) dissatisfaction. The overall objective results were excellent in 17 (47.2%), good in 11 (30.5%), fair in 6 (16.8%) and poor in 2 (5.5%) cases. A further advantage of this type of talocalcaneal fusion is the remaining range of motion in the neighbouring joints, at the ankle (in 75.7% the same or better ROM than preoperatively) and at Chopart joint (in 69.4% the same or better ROM than preoperatively). The fusion rate was high with 94.5%. CONCLUSION: The modified isolated talocalcaneal fusion without disruption at the Chopart joint is a simple surgical technique in the hand of the experienced surgeon. The subjective and objective mid-term results of this prospective follow-up study are comparable to other technique described in literature.
9580952 The involvement of matrix metalloproteinases and inflammation in lumbar disc herniation. 1998 Apr 15 STUDY DESIGN: Surgically obtained herniated lumbar disc specimens were stained with hematoxylin-eosin or toluidine blue (for detection of proteoglycans) or were immunostained with monoclonal antibodies (CD68), antihuman interstitial collagenase (matrix metalloproteinase [MMP]-1) and antihuman stromelysin (MMP-3). OBJECTIVE: To investigate the possible correlation of matrix metalloproteinase activity to granulation tissue formation and lumbar disc herniation, depending on the type of herniation. SUMMARY OF BACKGROUND DATA: Interstitial collagenase and stromelysin have been implicated in the degradation of the matrix of articular cartilage in rheumatoid arthritis, osteoarthritis and degenerated disc tissues. However, their role in the herniation of the intervertebral disc has received little study. METHODS: Twenty-one specimens of lumbar disc herniation (classified as protrusions, subligamentous extrusions, transligamentous extrusions, and sequestrations) and four nonherniated discs were stained with hematoxylin-eosin or toluidine blue or were immunostained with monoclonal antibodies to CD20, CD45RO, and CD68, anti-MMP-1, and anti-MMP-3, using the avidin-biotin-peroxidase complex method. The amount of granulation tissue and results of staining were graded to examine differences in histology among the four herniation types. RESULTS: In sequestration and transligamentous extrusion specimens, granulation tissue containing many CD68-positive macrophages was commonly observed. Most cells in granulation tissue, as well as chondrocytes, stained positively with anti-MMP-1 and anti-MMP-3 antibodies. Granulation tissue was less commonly observed in subligamentous extrusions and was absent from most protrusion specimens and all nonherniated specimens. B and T lymphocytes could not be demonstrated in granulation tissue. CONCLUSIONS: The increased staining of MMP-1 and MMP-3 associated with inflammatory cells of granulation tissue in herniated discs suggests a causal correlation of these proteinases to tissue degradation in herniation.
9564171 Mechanisms and functions of vitamin D. 1998 Feb The vitamin D hormone, 1,25-dihydroxyvitamin D3, functions by way of a nuclear receptor (vitamin D receptor [VDR]) in a manner analogous to the other members of the steroid-thyroid hormone superfamily. Although the vitamin D receptor has been cloned, its three-dimensional structure remains unknown. The VDR binds to the direct repeat response elements called DR-3 in the promoter region of target genes to stimulate or suppress transcription of those genes encoding for proteins that carry out a wide variety of functions. The binding of the VDR to a DR-3 requires the presence of its ligand and a companion protein, namely the RXR group of retinoid receptors. The RXR binds to the 5' arm of the response element while the VDR binds to the 3' arm. In addition, the transcription factor TFIIB has been shown to bind VDR but there is currently no evidence that a co-repressor or co-activator of VDR is also involved. Phosphorylation of VDR in the transcription complex occurs as does bending of the DNA prior to the initiation or suppression of transcription. As VDR has been detected in cells not previously thought to be target organs, scientists continue to discover new functions of vitamin D. Among these new functions are those noted in the immune system. Experiments in mice have illustrated that the autoimmune diseases of multiple sclerosis and rheumatoid arthritis can be successfully treated with the vitamin D hormone and its analogs. New experiments illustrating the use of the vitamin D hormone and its analogs in suppressing transplant rejection indicate that these compounds may be superior to cyclosporin and may not have the side effects attributed to the cyclosporin immunosuppression therapies.
9523575 Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a 1998 Apr Interleukin-6 (IL-6) is a proinflammatory cytokine whose synthesis is induced by a variety of stimuli including interleukin-1 (IL-1), substance P (SP), and histamine. Because IL-6 has been implicated in the etiopathology of different human diseases including multiple myeloma, rheumatoid arthritis, multiple sclerosis, acquired immunodeficiency syndrome dementia complex, and Alzheimer's disease, its inhibition may be of therapeutic interest. A main demand on an effective inhibitor of IL-6 expression is that it inhibits IL-6 synthesis independently of the inducing stimulus. We therefore used human astrocytoma cells to search for signal transduction cascades and transcription factors whose inhibition suppresses IL-6 synthesis after stimulation with three different inductors, IL-1beta, SP, and histamine. Whereas the antioxidant pyrrolidinedithiocarbamate was only able to inhibit IL-1beta-induced IL-6 expression, inhibition of protein kinase C prevented IL-6 expression induced by all three substances. Promoter deletion analysis revealed that IL-1beta-induced IL-6 expression required the transcription factor nuclear factor-kappaB (NF-kappaB), whereas SP- and histamine-induced IL-6 synthesis was essentially controlled by NF-IL-6. These findings suggest that inhibition of protein kinase C or a combinatory inhibition of NF-IL-6 and NF-kappaB binding are strategies to effectively suppress IL-6 synthesis. They therefore provide the basis for the development of antiinflammatory drugs used to treat disorders in which IL-6 is pathogenically involved.
11757824 Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for 2001 Dec Over the past year, human studies have confirmed and expanded the involvement of macrophage migration inhibitory factor (MIF) in a number of diseases that had originally been studied in animals. In addition to sepsis, rheumatoid arthritis, glomerulonephritis and inflammatory lung disease, elevated MIF levels have been described in patients suffering from ulcerative colitis, inflammatory neurological diseases and cancer. Cellular studies indicate that in addition to macrophages, MIF affects the activities of CD4+ and CD8+ T cells, natural killer cells, fibroblasts and endothelial cells, actions that may explain the contribution of MIF to inflammatory diseases and cancer. Molecular studies have identified direct interactions between MIF and several intracellular regulatory proteins (Jab1, PAG and p53) that control cellular growth and proliferation; however, how interactions with these proteins fit into a general scheme to explain MIF's biological activity has not been elucidated. The three-dimensional structure of MIF has offered some surprising clues and if the potential enzymatic sites identified are involved with MIF-associated diseases, they may provide good targets for therapeutic intervention.
11580850 Diversity of HLA among Taiwan's indigenous tribes and the Ivatans in the Philippines. 2001 Jul Taiwan's indigenous tribes, especially the east coast tribes are not only closely related to Oceania but also with the Australian aborigines. The Ivatans of the Batan Islands in the Philippines are closely related to the Yami tribe of Taiwan as cultural and anthropological studies have shown. Many DRB1 alleles (*15021, *16021, *0404, *04051, *11011, *12021, *1401, *08032) have high allele frequencies (>20%) in certain tribes, suggesting Taiwan's indigenous tribes are homogeneous populations. These high frequency DRB1 alleles and also some HLA-A-B-DR haplotypes found in Taiwan's indigenous tribes are also found in Oceania, Australian aborigines, south and north east Asians and American Indians, lending further support to our previous findings that Taiwan's indigenous tribes are more or less genetically related to both northern and southern Asians, possibly as well as Amerindians. HLA-A*2402 with a remarkably high frequency among Taiwan's indigenous tribes (52.1% approximately 86.3%), especially the central mountain tribes, possibly represents not only founder effects and population bottlenecks, but also positive selection of the allele. Although the Ami tribe has the highest ever reported frequencies of the DRB1*0404 and DRB1*0405, these alleles have not been found to be associated with rheumatoid arthritis as previously described for Caucasians. In addition, DRB1*1401 has a high frequency in most tribes but is not associated with psoriasis as previously indicated in some studies, suggesting the involvement of some additional genetic and/or environmental factors mechanism in the development of these diseases.
11528011 The anti-inflammatory effects of circulating fatty acids in obstructive jaundice: similari 2001 Sep Rheumatoid arthritis (RA) is ameliorated during both obstructive jaundice and pregnancy. Previous studies of polymorphonuclear leukocyte (PMN) function during pregnancy have shown reductions in the stimulated release of arachidonic acid (AA) and leukotriene B4 (LTB4), and lower NADPH oxidase activity. These changes may account for the amelioration of RA. The cause of this reduction in PMN function appears to be a progressive change in circulating fatty acids (FA), with a reduction in polyunsaturated FA, predominantly AA. The NADPH oxidase responsible for the respiratory burst has a direct requirement for polyunsaturated FA, particularly AA. We investigated whether the same changes in PMN function and FA, occur during obstructive jaundice. Patients with biliary obstructions were investigated before and after surgical correction (n=14). Obstructive jaundice caused significant changes in the proportions of serum and cellular FA. There was a striking reduction in polyunsaturated FA, particularly AA (48% in serum, p<0.001; 42% in PMNs, p<0.001) and an increase in mono-unsaturated oleic acid (24% in serum, p<0.001; 15% in PMNs, p<0.005). Similar changes occurred in mononuclear cell FA. Jaundice also caused a significant reduction in PMN function. Respiratory burst activity was reduced by between 32% and 38% in response to physiological and non-physiological stimuli, and there were similar significant reductions in the release of AA and LTB4. These changes in stimulated PMN function were evident whether or not the cells were first primed with tumour necrosis factor alpha (TNFalpha). Incubation of PMNs from healthy donors in pooled serum from patients with obstructive jaundice caused a reduction of 32% in cellular AA and 38% in NADPH oxidase activity. These findings support the idea that circulating FA can regulate PMN inflammatory responsiveness. The FA-induced attenuation in PMN activity in both jaundice and pregnancy may explain their ameliorating effects upon RA.
11522796 The transcription factor C/EBPbeta is essential for inducible expression of the cox-2 gene 2001 Nov 2 Cyclooxygenase-2 (COX-2) is the rate-limiting enzyme for the inducible synthesis of prostaglandins, and its up-regulated activity is thought to play a pathological role in diseases such as inflammatory bowel disease, rheumatoid arthritis, and cancer. Regulation of COX-2 expression is complex and appears to involve diversified mechanisms in different cell types and conditions. Here we make use of immortalized macrophages and fibroblasts that we have generated from C/EBPbeta-deficient mice to directly test and compare the specific role played by this factor in inducible COX-2 expression in these two cell types. We could demonstrate that COX-2 mRNA induction and promoter activity were profoundly impaired in C/EBPbeta(-/-) macrophages and could be rescued by expression of C/EBPbeta. The obligatory role of C/EBPbeta in COX-2 expression appeared to be mediated exclusively by the C/EBP element located at positions -138/-130 of the murine cox-2 promoter, and did not involve altered activity at the level of the other promoter elements described previously (the -402/-392 NF-kappaB site, the -59/-48 CRE/E box element, and a potential second C/EBP site located at positions -93/-85). In contrast, COX-2 induction was completely normal in C/EBPbeta-deficient fibroblasts, thus highlighting the diversity of cell-specific molecular mechanisms in determining inducible COX-2 expression and prostaglandins production.