Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 9675664 | The case against routine post-operative therapy for prevention of recurrence in Crohn's di | 1998 Apr | Crohn's disease is inevitably characterized by episodes of relapse followed by remission. The majority of patients will require at least one resection, unfortunately many will have, at some time in the future, further recurrences requiring additional surgery. Faced with this clinical situation, the physician or surgeon may respond to the therapeutic imperative, i.e., it is better to do something rather than to do nothing at all (i.e., treat the patient). Because of these factors, various authors have suggested that the aminosalicylates or, in certain cases, azathioprine, should be prescribed following resection. From a health system point of view, the case for maintenance therapy must be reviewed against several criteria. First, the therapy to be prescribed must be safe for patients over the long term. For the most part, the safety profile of mesalamine has been well established. There is also increasing evidence for the safety of azathioprine when used in chronic inflammatory diseases such as rheumatoid arthritis. Second, there must be objective evidence of efficacy as assessed by randomized controlled, double-blind trials. To date, several trials have been performed, unfortunately, the most recent have only been reported in abstract form. The results of the trials have been contradictory with a mixture of positive and negative findings. There is a lack of consistency for both the dose response and preferred disease site, the use of placebos, the evaluation of outcome and the statistical analysis. Third, the cost-benefit ratio must favour the therapy. Calculation of the number to reat (NNT) to prevent one recurrence is often helpful. Finally, compliance in a group of patients who often decide on surgery so that they can stop taking medication must be considered. A variety of criteria have been developed to assist in making choices regarding prophylaxis. The first relates to the ease of treating the patient with recurrence. Some patients will respond promptly to conventional therapy and enter remission. Unfortunately, this is not the case for the majority of patients. We lack predictors of response. The second concerns the issue as to whether or not the condition to be prevented, recurrence, is a "serious" event. There would be little discussion of that issue at an IBD meeting! The third considers the possibility of adverse events related to the prophylaxis. Again, there does not appear to be concern related to safety. It is the final criterion regarding effectiveness that balances the argument against a routine recommendation for post-operative maintenance therapy. | |
| 9634701 | Solution structure of the heparin-binding domain of vascular endothelial growth factor. | 1998 May 15 | BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and is a potent angiogenic and vascular permeabilizing factor. VEGF is also an important mediator of pathological angiogenesis associated with cancer, rheumatoid arthritis and proliferative retinopathy. The binding of VEGF to its two known receptors, KDR and Flt-1, is modulated by cell-surface-associated heparin-like glycosaminoglycans and exogenous heparin or heparan sulfate. Heparin binding to VEGF165, the most abundantly expressed isoform of VEGF, has been localized to the carboxy-terminal 55 residues; plasmin cleavage of VEGF165 yields a homodimeric 110-residue amino-terminal receptor-binding domain (VEGF110) and two 55-residue carboxy-terminal heparin-binding fragments. The endothelial cell mitogenic potency of VEGF110 is decreased significantly relative to VEGF165, indicating that the heparin-binding domains are critical for stimulating endothelial cell proliferation. RESULTS: The solution structure of the 55-residue heparin-binding domain of VEGF165 has been solved using data from two-dimensional homonuclear and three-dimensional heteronuclear NMR spectroscopy. The structure has two subdomains, each containing two disulfide bridges and a short two-stranded antiparallel beta sheet; the carboxy-terminal subdomain also contains a short alpha helix. Hydrophobic interactions are limited to sidechains packing against the disulfide bridges. CONCLUSIONS: The heparin-binding domain of VEGF has no significant sequence or structural similarity to any known proteins and thus represents a novel heparin-binding domain. Most of the positively charged amino acid sidechains are localized on one side of the carboxy-terminal subdomain or on an adjacent disordered loop in the amino-terminal subdomain. The observed distribution of surface charges suggests that these residues constitute a heparin interaction site. | |
| 9486988 | Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. | 1998 Mar 1 | Transcription factors of the NF-kappaB/Rel family are critical for inducible expression of multiple genes involved in inflammatory responses. Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription factor NF-kappaB is a target of sulfasalazine-mediated immunosuppression. Treatment of SW620 colon cells with sulfasalazine inhibited TNFalpha-, LPS-, or phorbol ester- induced NF-kappaB activation. NF-kappaB-dependent transcription was inhibited by sulfasalazine at micro- to millimolar concentrations. In contrast, 5-aminosalicylic acid or sulfapyridine did not block NF-kappaB activation at all doses tested. TNFalpha-induced nuclear translocation of NF-kappaB was prevented by sulfasalazine through inhibition of IkappaBalpha degradation. When blocking proteasome-mediated degradation of IkappaBalpha, we could demonstrate that sulfasalazine interfered with IkappaBalpha phosphorylation, suggesting a direct effect on an IkappaBalpha kinase or on an upstream signal. Inhibition of NF-kappaB activation seems to be specific since other DNA-binding activities such as AP1 were not affected. These results demonstrate that sulfasalazine is a potent and specific inhibitor of NF-kappaB activation, and thus may explain some of the known biological properties of sulfasalazine. | |
| 9291420 | Cellular immune reactivities in women with silicone breast implants: a preliminary investi | 1997 Aug | BACKGROUND: Surgical implantation of silicone breast prostheses has been conducted and considered safe for over 30 years. Some implant recipients, however, complain of a group of symptoms similar to those observed in connective tissue disorders, rheumatoid arthritis, systemic lupus erythematosus, or polymyositis. To date, immunologic sequelae have not been confirmed and remain controversial. OBJECTIVE: To examine an autoimmune-like basis for the "silicone associated disease" reported by some women with silicone breast prostheses. METHODS: Proliferative responses of peripheral blood mononuclear cells against a panel of control and connective tissue proteins and to compounds common to silicone prostheses were measured in 26 women who received silicone breast implants (with implants in place an average of 166.4 [standard deviation (SD) 58.3] months), and 23 age-matched and sex-matched healthy controls. RESULTS: The frequency and intensity of cellular immune responses against collagen I, collagen III, fibrinogen, and fibronectin were significantly increased in silicone breast implant recipients versus controls. In implant subjects, the highest frequency of immune reactivity was directed against collagen I (11/26, 42%) with collagen III being the most immunostimulatory self-antigen with a mean stimulation index (SI) of 8.2 [95% confidence interval (95% CI) 3.2]. In addition, 10/26 (39%) of the implant recipients responded to more than one of the connective tissue antigens versus 0/23 (0%, P = .0007) healthy controls. Immunologic reactivities to other antigens, including silicone-based compounds, were remarkably similar. CONCLUSIONS: The identification of self-reactivity towards these connective tissue antigens may provide important information for attempts at associating silicone breast implants with disease. | |
| 9063885 | Variations in oligosaccharide-protein interactions in immunoglobulin G determine the site- | 1997 Feb 11 | Glycoproteins, such as immunoglobulin G (IgG), consist of an ensemble of glycosylated variants, or glycoforms, which have different oligosaccharides attached to a common peptide. Alterations in the normal glycoform populations of IgG are associated with certain disease states, notably rheumatoid arthritis and its remission during pregnancy. In this paper, we show that two sets of IgG Fc glycoforms have quite different physical properties. The first set has 1,6 arm terminal galactose residues which interact with the protein, resulting in glycan binding to the protein surface, in agreement with the crystal structure. In contrast, the second set of glycoforms which lack galactose does not bind to the protein surface. Recently developed HPLC techniques combined with enzymatic digestion and mass spectrometry have been used to assign the glycan structures on IgG, Fab, and Fc. Comparison of Fab with Fc shows that glycosylation is site-specific. Two major glycan structures are present on Fab (fucosylated digalacto-bianntenary with and without bisect) and three on Fc (fucosylated agalacto-, 1,6 arm monogalacto-, and digalacto-bianntenary). In comparison to Fab, Fc glycans contain (i) lower levels of bisecting GlcNAc, (ii) lower levels of galactose, (iii) higher than expected levels of 1,6 arm galactose relative to 1,3 arm, and (iv) no 1,6 arm sialylation. We interpret these differences to indicate a role for both the protein quaternary structure and specific protein-glycan interactions in determining the glycoform populations. NMR relaxation measurements have been used to probe the mobility of the glycans in the Fc. By comparing two samples with different glycoform populations, we conclude that this mobility is dependent on the primary sequence of the glycan. Glycans carrying a galactose residue on the 1,6 arm have relaxation properties very similar to those of the peptide backbone and thus do not have independent motion. Glycans lacking galactose have relaxation rates 30 times slower than that of the peptide and thus a higher degree of mobility. These agalactosyl glycans do not interact with the protein, resulting in exposure of previously covered regions of the peptide surface and making the glycan more accessible. This implies that at the early stages of glycan processing the Fc glycans are mobile and only partially protected by the protein quaternary structure. Immobilization of the glycans occurs as a consequence of addition of galactose to the 1,6 arm and results in increased protection. | |
| 9093774 | Clinical significance of serum thrombomodulin levels in patients with systemic rheumatic d | 1997 Jan | OBJECTIVE: To determine the soluble thrombomodulin (TM) level in the sera of patients with systemic rheumatic diseases and to analyze its relationship with clinical and laboratory parameters in patients with systemic lupus erythematosus (SLE). METHODS: Serum levels of TM were measured by an enzyme-linked immunosorbent assay in 124 patients with SLE and in 237 patients with systemic rheumatic diseases other than SLE. RESULTS: The frequency of patients with high TM levels (> or = 4.5 FU/ml) was 21% in SLE, 16% in rheumatoid arthritis (RA), 12% in Sjögren's syndrome (SS), and 4% in systemic sclerosis (SSc). The TM levels were significantly higher in SLE patients with the following abnormalities in their past history or present illness: persistent proteinuria, cellular casts, positive anti-dsDNA antibodies (p < 0.001), hypoalbuminemia, decreased creatinine clearance (Ccr), positive anti-Sm antibody, positive immune complex, leukopenia (p < 0.01), pericarditis, oral ulcer, fluorescent anti-nuclear antibody (FANA), decreased C3 and arthralgia (p < 0.05). The serum TM levels in SLE showed a direct correlation with the urinary protein level (p < 0.01) and serum creatinine level (p < 0.01), and an inverse correlation with the serum albumin level (p < 0.01) and complement C3 level (p < 0.05). In SLE patients with active disease, the median TM level at the time of admission (5.9 FU/ml) was significantly higher than at 6 months before admission (3.8 FU/ml, p < 0.01) and at 6 months after admission (4.2 FU/ml, p < 0.001). Moreover, elevation and reduction of the TM level in lupus patients with active disease parallelled that of the SLE disease activity index (SLEDAI). In two representative SLE cases, one with lupus nephritis (LN) and the other with thrombocytopenia without LN, elevated TM levels at disease flare were reduced along with the amelioration of the disease by administration of corticosteroids. CONCLUSIONS: The serum TM level is closely associated with SLE activity and appears to be useful as a new disease activity parameter of SLE. | |
| 9655104 | Revision total shoulder arthroplasty for the treatment of glenoid arthrosis. | 1998 Jun | The development of painful glenoid arthrosis is the most common reason for reoperation after replacement of the humeral head. We performed twenty-two revision total shoulder arthroplasties, between 1983 and 1992, for the treatment of painful glenoid arthrosis in shoulders that had a prosthetic replacement of the humeral head. Eighteen shoulders (seventeen patients) were included in the study as their preoperative and operative records were complete and they had been followed for at least two years (mean, 5.5 years; range, 2.3 to 10.0 years). The indications for the hemiarthroplasty were trauma (ten shoulders), osteoarthrosis (four), rheumatoid arthritis (two), and osteonecrosis secondary to the use of steroids (two). The mean interval between the hemiarthroplasty and the total shoulder replacement was 4.4 years (range, 0.8 to 12.7 years). The mean score for pain in the shoulder decreased from 4.3 points before the revision to 2.2 points after it (p = 0.0001). The mean active abduction increased from 94 degrees before the revision to 124 degrees after it (p = 0.01), and the mean external rotation increased from 32 to 58 degrees (p = 0.007). Two shoulders needed another operation after the revision because of a late infection in one and particulate synovitis associated with instability in the other. With the numbers available for study, we did not detect a significant difference in pain relief and range of motion with respect to gender, diagnosis, subluxation, or the presence of periprosthetic radiolucency. Our findings indicate that most patients with painful glenoid arthrosis after a hemiarthroplasty have marked pain relief and improvement in motion after revision to a total shoulder replacement. However, seven of the eighteen shoulders that had this procedure had an unsatisfactory result due to a limited range of motion or the need for a subsequent operation. Therefore, long-term studies are necessary to evaluate the durability of total shoulder replacement in this group of patients. | |
| 11426028 | Hyperhomocysteinaemia in Behçet's disease. | 2001 Jun | OBJECTIVE: Arterial and venous thrombosis are among the clinical features of Behçet's disease (BD), the pathogenesis of which is not completely understood. In this study, we investigated whether hyperhomocysteinaemia, being a well known risk factor for thrombosis, is also a contributive risk factor for the arterial and venous thrombosis of BD. METHODS: Eighty-four patients fulfilling the criteria of the International Study Group for Behçet's Disease (54 males, 30 females, mean age 36+/-9 yr) were enrolled. All the patients were carefully screened for a history of venous thrombosis and were separated into two groups with respect to thrombosis history. Thirty-six healthy individuals (23 males, 13 females), matched for age and sex with the BD group, were included as a negative control group. Patients were excluded if they had any condition that might affect plasma homocysteine concentration. As methotrexate (MTX) causes hyperhomocysteinaemia, we also included 29 rheumatoid arthritis patients (five males, 24 females) receiving MTX weekly. Fasting plasma homocysteine concentrations were measured by high-performance liquid chromatography. The data were analysed with the chi(2) test and Student's t-test. RESULTS: The highest homocysteine concentrations were found in the MTX group (17.5+/-5.3 micromol/l). Mean plasma homocysteine concentrations in BD patients were significantly higher than in the healthy controls (11.5+/-5.3 vs. 8.8+/-3.1 micromol/l, P<0.001). Among BD patients with a history of thrombosis, 20 of 31 (64%) had hyperhomocysteinaemia, and this was significantly higher than in those without thrombosis (9%). On the other hand, there was no significant difference between patients with non-thrombotic BD and healthy controls (P>0.05). In patients with thrombosis, we found no correlation between the duration of the post-thrombotic period and homocysteine concentration. Among all the variables investigated, only hyperhomocysteinaemia was found to be related to thrombosis. CONCLUSION: Hyperhomocysteinaemia may be assumed to be an independent risk factor for venous thrombosis in BD. Unlike the factor V Leiden mutation, hyperhomocysteinaemia is a correctable risk factor. This finding might lead to new avenues in the prophylaxis of thrombosis in BD. | |
| 11310944 | Lack of congruence in the ratings of patients' health status by patients and their physici | 2001 Mar | PURPOSE: The purpose of this study was to examine if physician assessments of their patients' health status after the medical encounter are comparable to their patients' self-assessment of their own health. METHODS: Consecutive patients with musculoskeletal diseases were recruited when they attended 1 of the rheumatology outpatient clinics selected for the study. Five physicians participated in the study, 4 based at an academic center and 1 in the community. Patients were interviewed after seeing the physician; they completed health status questionnaires (mHAQ and SF-12) and rated their pain, worry about disease, and overall health status on visual analog scales. Standard gamble techniques were used to obtain patient utilities in relation to their health status, "gambling" on the probability of obtaining perfect health from an intervention with varying risks of death. After the medical encounter, physicians were asked to rate their patients' health status with similar instruments and with standard gamble elicitation techniques, blinded to the patients' responses. RESULTS: A total of 105 patients participated in the study; 70% were female; mean age was 54+/-16 years; 64% had a connective tissue disease, most commonly rheumatoid arthritis; and the other diseases in this group included soft tissue rheumatism, osteoarthritis, or low back pain. Statistically significant differences were observed between patient and physician ratings for pain, overall health, and standard gamble. On average, physicians rated their patients' health status higher than the patients themselves and were less willing to gamble on the risk of death versus perfect health. Intraclass correlation coefficients (ICC) were low: 0.42 for pain, 0.11 for worry, 0.11 for overall health, and 0.04 for standard gamble utilities. Similar findings were observed when subgroup analysis was performed for individual physicians and for patients with connective tissue diseases. No specific patient characteristic consistently related to increased divergence in the ratings. CONCLUSIONS: These findings suggest that the communication between physicians and their patients at the time of the medical encounter needs to be enhanced. An understanding of their patients' health perceptions may assist physicians in suggesting appropriate interventions, taking into account their patients' benefit-risk preferences. | |
| 11204434 | Efficacy of etanercept for wear debris-induced osteolysis. | 2001 Feb | A major limitation of total joint arthroplasty is that up to 20% of patients require revision surgery to correct prosthetic loosening. Aseptic loosening is believed to result from the phagocytosis of wear debris particles by macrophages, which secrete proinflammatory cytokines that stimulate osteolysis. Tumor necrosis factor alpha (TNF-alpha) has been shown to be one of the prominent cytokines in this cascade and to be involved critically in the generation of particle-induced osteolysis. Etanercept is a soluble inhibitor of TNF-alpha, which is widely used for the treatment of rheumatoid arthritis. Here, we show this agent's ability to prevent wear debris-induced osteolysis. In vitro we show that Etanercept can inhibit directly osteoclastic bone resorption in a bone wafer pit assay, as well as cytokine production from titanium (Ti)-stimulated macrophages. Using a quantitative in vivo model of wear debris-induced osteolysis, we show that Etanercept prevents bone resorption and osteoclastogenesis. In mice treated with Etanercept at the time of osteolysis induction, bone resorption and osteoclast numbers were reduced to background levels in both normal and human TNF-alpha (hTNF-alpha) transgenic mice. In an effort to evaluate its effect on established osteolysis, Etanercept was administered 5 days after Ti implantation, and we observed that further osteolysis was prevented. These data support the concept that TNF-alpha is involved critically in osteoclastogenesis and bone resorption during periprosthetic osteolysis and suggest that soluble TNF-alpha inhibitors may be useful as therapeutic agents for the treatment of prosthetic loosening in humans. | |
| 10950048 | Higher expression of glucocorticoid receptor in peripheral mononuclear cells in inflammato | 2000 Aug | OBJECTIVE: Glucocorticoids are widely used in the treatment of inflammatory bowel disease (IBD). Up- and down-regulated expression of glucocorticoid receptors (GR) has been reported for different chronic inflammatory diseases. The aim of this study was to investigate the expression of GR and their apparent dissociation constant (Kd) in patients with IBD. METHODS: Thirty-nine patients with IBD (22 with ulcerative colitis, 17 with Crohn's disease) and 35 normal controls were studied. Twenty-five patients did not receive steroids, 14 patients were treated with steroids. Peripheral blood mononuclear cells from patients and controls were isolated using the Ficoll-Hypaque gradient and a whole cell [3H]-dexamethasone binding assay and Scatchard plot analysis were performed to assess GR number and the apparent dissociation constant. Results were expressed as mean +/- standard deviation. RESULTS: Normal controls showed an expression of 3,969 +/- 1,555 GR per cell with an apparent dissociation constant of 6.16 +/- 3.8 nmol/L. IBD patients without steroids had a significant increase both in the expression of GR per cell (6,401 +/- 2,344; p < 0.0001; Wilcoxon-Mann-Whitney test) and in the apparent dissociation constant (11.02 +/- 7.57 nmol/L; p = 0.006). Expression of GR in IBD patients was suppressed to normal levels under steroid treatment (4,594 +/- 2,237; p = 0.024), but Kd remained elevated (13.56 +/- 9.05 nmol/L). Plasma cortisol levels were not different between IBD patients and the control group. CONCLUSIONS: Our data show a systemic increase in GR expression and a decrease in the affinity to the GR in IBD, in contrast to other inflammatory diseases such as rheumatoid arthritis and asthma. These changes point towards a systemic character of IBD, which might be considered in a decision between topical and systemic treatment. | |
| 10930882 | [Imaging of chronic hip pain in adults]. | 2000 Mar | Adult hip pathologies are mainly represented by the degenerative disease, so called "osteoarthrosis, or more precisely coxarthrosis". The means of imaging are exposed, according to their specific value: X Rays (measurement of the characteristic angles of the adult hip), Arthrography, CT Scanner, Arthro-CT Scanner, MRI, Bone Scintigraphy, Ultrasonography. Clinical findings differentiate a mechanical syndrome and an inflammatory syndrome. The coxarthrosis is the most frequent, under two forms: primary (idiopathic) coxarthrosis and secondary coxarthrosis. Primary (idiopathic) coxarthrosis has a localised narrowing of the joint space, osteophyte formation, subchondral sclerosis, cyst formation. The destruction progresses slowly, in 10 to 15 years leading to a complete destruction. Bilaterality is frequent. it is treated with total hip prosthesis. There is a rapid form (1 to 2 years) (Postel's Disease). Secondary coxarthrosis occurs after architectural vice, chondral diseases, lack of balance between the size of the head and the acetabulum as in the case of previous fracture or dislocation, avascular bone necrosis of the head of the femur, Paget's disease. Calcium pyrophosphate Deposition disease (CPPD) involves mostly aged women, and also leads to cox-arthrosis. Avascular bone necrosis of the head of the femur involves young adults. Bilateral involvement are frequent. MRI is the most sensitive and the most specific means of early diagnosis, The area of bone necrosis appears as well defined modifications of the upper head of the femur, precisely surrounded by a low signal intensity line on both Ti and T2 weighted imaging. MRI shows articular effusion, bone marrow edema. Scintigraphy gives early findings which are a characteristic, but non specific, hot spot. CT scanner is used for hip destruction evaluation. o Algodystrophy: transient osteoporosis of the hip has a cyclic course, lasting 3 to 9 months. MRI shows an inflammatory pattern in the area of the process(dark in Ti and white in T2, with positive Gadolinium response). Scintigraphy is positive. Staphylococcus location in the hip can be acute or chronic. MRI shows joint effusion, cystic formation and subchondral non specific modifications. Tuberculosis of the hip joint is relatively rare. Greater trochanteric tuberculous involvement is possible under special contexts. Chronic Inflammatory diseases are represented by Rheumatoid Arthritis, Spondylarthritis and other chronic inflammatory diseases. Synovial tumors such as Pigmented Villo Nodular Synovitis, Primary Osteochondromatosis, synovial sarcoma have special presentations. The subchondral bone can be involved by amorphous depositions such as in tophaceous gout, different varieties of lipidosis, amyloidosis, reticulo histiocytosis. Pen arthropathies are enthesopathies in the anterior rectus tendon, calcifying tendonitis (not to be confused with calcifying soft tissue tumor/chondrosarcoma). The pelvis bone and the femur are involved by primary and secondary tumors or by insufficiency fractures which can mislead to hip pathologies. | |
| 10917903 | Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents seru | 2000 Aug | Previous studies reveal that supplementation of human diets with gamma-linolenic acid (GLA) reduces the generation of lipid mediators of inflammation and attenuates clinical symptoms of chronic inflammatory disorders such as rheumatoid arthritis. However, we have shown that supplementation with this same fatty acid also causes a marked increase in serum arachidonate (AA) levels, a potentially harmful side effect. The objective of this study was to design a supplementation strategy that maintained the capacity of GLA to reduce lipid mediators without causing elevations in serum AA levels. Initial in vitro studies utilizing HEP-G2 liver cells revealed that addition of eicosapentaenoic acid (EPA) blocked Delta-5-desaturase activity, the terminal enzymatic step in AA synthesis. To test the in vivo effects of a GLA and EPA combination in humans, adult volunteers consuming controlled diets supplemented these diets with 3.0 g/d of GLA and EPA. This supplementation strategy significantly increased serum levels of EPA, but did not increase AA levels. EPA and the elongation product of GLA, dihomo-gamma-linolenic acid (DGLA) levels in neutrophil glycerolipids increased significantly during the 3-wk supplementation period. Neutrophils isolated from volunteers fed diets supplemented with GLA and EPA released similar quantities of AA, but synthesized significantly lower quantities of leukotrienes compared with their neutrophils before supplementation. This study revealed that a GLA and EPA supplement combination may be utilized to reduce the synthesis of proinflammatory AA metabolites, and importantly, not induce potentially harmful increases in serum AA levels. | |
| 10796633 | Dietary marine fatty acids (fish oil) for asthma. | 2000 | BACKGROUND: Epidemiological studies suggest that a diet high in marine fatty acids (fish oil) may have beneficial effects on inflammatory conditions such as rheumatoid arthritis and possibly asthma. OBJECTIVES: 1. To determine the effect of marine n-3 fatty acid (fish oil) supplementation in asthma. 2. To determine the effect of a diet high in fish oil in asthma. SEARCH STRATEGY: The Cochrane Airways Review Group register was search using the terms: marine fatty acids OR diet OR nutrition OR fish oil OR eicosapentaenoic acid OR EPA. Bibliographies of retrieved trials were searched and fish oil manufacturers contacted. SELECTION CRITERIA: Randomised controlled trials in patients with asthma more than two years of age were included. The study duration had to be in excess of 4 weeks. Double blind trials were preferred, but single-blind and open trials were also reviewed for possible inclusion. Three reviewers read each paper, blind to its identity. Decisions concerning inclusion were made by simple majority. Quality assessment was performed by all three reviewers independently. DATA COLLECTION AND ANALYSIS: The only comparison possible was between marine n-3 fatty acid supplementation and placebo. There were insufficient trials to examine dietary manipulation alone. MAIN RESULTS: Eight randomised controlled trials conducted between 1986 and 1998 satisfied the inclusion criteria. Six were of parallel design and two were cross-over studies. Seven compared fish oil with placebo whilst one compared high dose vs low dose marine n-3 fatty acid supplementation. None of the included studies reported asthma exacerbations, health status or hospital admissions. There was no consistent effect on any of the analyzable outcomes: FEV1, peak flow rate, asthma symptoms, asthma medication use or bronchial hyper reactivity. The single study performed in children also combined dietary manipulation with fish oil supplementation and showed improved peak flow and reduced asthma medication use. There were no adverse events associated with fish oil supplements. REVIEWER'S CONCLUSIONS: There is little evidence to recommend that people with asthma supplement or modify their dietary intake of marine n-3 fatty acids (fish oil) in order to improve their asthma control. Equally, there is no evidence that they are at risk if they do so. | |
| 10769104 | Glucocorticoid-induced osteoporosis: is the bone density decrease the only explanation? | 2000 | BACKGROUND: Glucocorticoids may increase bone fragility via mechanisms independent from their bone mass reducing effect. OBJECTIVE: To study relationships between osteoporotic fractures and bone mineral density in patients on long-term glucocorticoid therapy. PATIENTS AND METHODS: We studied 121 women with a mean age of 60.4 +/- 14.3 years on long-term glucocorticoid therapy (cumulative dose > or = 1 g of prednisone equivalent, duration > or = 6 months) for rheumatoid arthritis (n = 38), polymyalgia rheumatica or giant cell arteritis (n = 26), connective tissue disease (n = 15), asthma (n = 14), another inflammatory joint disease (n = 14), or another condition (n = 14). The control group was composed of 125 subjects who had the same mean age and met the same exclusion criteria as the case group. Bone mineral density was measured at the lumbar spine and femoral neck using a Hologic QDR 4500 unit. In subjects with back pain, radiographs of the thoracic and lumbar spine were obtained to look for fractures. RESULTS: The odds ratio for a bone mineral density decrease of one standard deviation at the femoral neck was 1.68 (1.20-2.35) in patients with a cumulative glucocorticoid dose of 10 g of prednisone equivalent and 1.67 (1.22-2.29) in those with a glucocorticoid therapy duration of 2 years. Sixty-eight fractures were recorded in 56 patients (46% of the overall patient group). Even after adjustment on age, glucocorticoid therapy duration, and dose, mean bone mineral density values at the lumbar spine and femoral neck were significantly lower in the subgroup of patients with fractures than in the subgroup without fractures. Sensitivity and specificity of bone mineral density at the femoral neck and/or lumbar spine for the diagnosis of vertebral fracture and/or peripheral fracture were 73% and 51%, respectively. In the stepwise logistic regression model, factors explaining the presence of fractures were as follows, in hierarchical order: age; absence of calcium/vitamin D supplementation, femoral neck T-score, and glucocorticoid dose. CONCLUSION: Our data are compelling evidence that bone mineral density is a major determinant of the fracture risk in patients with glucocorticoid-induced osteoporosis. | |
| 10692062 | Lichenoid and granulomatous dermatitis. | 2000 Feb | BACKGROUND: The prototypic lichenoid eruptions, lichen planus (LP), lichenoid drug eruptions, secondary syphilis, and collagen vascular disease, are defined histologically by a band-like lymphocytic infiltrate in close apposition to the epidermis. We describe a novel form of lichenoid dermatitis with a granulomatous component. DESIGN: Skin biopsies from 40 patients demonstrating a band-like lymphocytic infiltrate with concomitant granulomatous inflammation were encountered over 4 years. Clinicians were contacted to elucidate underlying triggers and medical illnesses. RESULTS: A lichenoid dermatitis, a linear eruption, vasculitis, annular erythema, and erythroderma were among the clinical presentations. A drug-based etiology was implicated in 14 cases: the drugs included antibiotics, lipid-lowering agents, anti-inflammatory drugs, antihistamines, hydroxychloroquine sulfate, and angiotensin-converting enzyme inhibitors. Over one-third of patients with drug-related eruptions had other medical illnesses associated with cutaneous granulomatous inflammation, namely rheumatoid arthritis (RA), Crohn's disease, hepatitis C, diabetes mellitus, and thyroiditis. A microbial trigger was implicated in 12 patients in the context of infective id reactions to herpes zoster, Epstein-Barr virus (EBV), or streptococci, or active infections by Mycobacterium tuberculosis, M. leprae, fungi, and spirochetes. The remainder had hepatobiliary disease and RA without obvious exogenous triggers, cutaneous T-cell lymphoma (CTCL), and idiopathic lichenoid eruptions (i.e. LP, lichen nitidus, and lichen striatus). One patient with LP had underlying multicentric reticulohistiocytosis. The histiocytic infiltrate assumed one or more of five light microscopic patterns: (i) superficially disposed loose histiocytic aggregates; (ii) cohesive granulomata within zones of band-like lymphocytic infiltration with or without deeper dermal extension; (iii) a diffuse interstitial pattern; (iv) scattered singly disposed giant cells; and (v) granulomatous vasculitis. Additional features included lymphocytic eccrine hidradenitis in those patients with drug reactions, hepatobiliary disease, and antecedent viral illnesses, tissue eosinophilia and erythrocyte extravasation in drug hypersensitivity, granulomatous vasculitis in patients with microbial triggers, drug hypersensitivity or RA, and lymphoid atypia in lesions of CTCL or drug hypersensitivity. CONCLUSIONS: The cutaneous lichenoid and granulomatous reaction may reflect hepatobiliary disease, endocrinopathy, RA, Crohn's disease, infection, or a drug reaction. One-fifth of cases represent idiopathic lichenoid disorders. Lymphoproliferative disease or pseudolymphomatous drug reactions must be considered in those cases showing lymphoid atypia. | |
| 10473520 | Detection of borna disease virus-reactive antibodies from patients with psychiatric disord | 1999 Sep | The prevalence of Borna disease virus (BDV)-specific antibodies among patients with psychiatric disorders and healthy individuals has varied in several reports using several different serological assay methods. A reliable and specific method for anti-BDV antibodies needs to be developed to clarify the pathological significance of BDV infections in humans. We developed a new electrochemiluminescence immunoassay (ECLIA) for the antibody to BDV that uses two recombinant proteins of BDV, p40 and p24 (full length). Using this ECLIA, we examined 3,476 serum samples from humans with various diseases and 917 sera from blood donors in Japan for the presence of anti-BDV antibodies. By ECLIA, 26 (3.08%) of 845 schizophrenia patients and 9 (3.59%) of 251 patients with mood disorders were seropositive for BDV. Among 323 patients with other psychiatric diseases, 114 with neurological diseases, 75 with chronic fatigue syndrome, 85 human immunodeficiency virus-infected patients, 50 with autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosis and 17 with leprosy, there was no positive case except one case each with alcohol addiction, AIDS, and dementia. Although 19 (1.36%) of 1,393 patients with various ocular diseases, 10 (1.09%) of 917 blood donors, and 3 (4.55%) of 66 multitransfused patients were seropositive for BDV-specific antigen, high levels of seroprevalence in schizophrenia patients and young patients (16 to 59 years old) with mood disorders were statistically significant. The immunoreactivity of seropositive sera could be verified for specificity by blocking with soluble p40 and/or p24 recombinant protein. Anti-p24 antibody was more frequent than p40 antibody in most cases, and in some psychotic patients antibody profiles showed only p40 antibody. Although serum positive for both p40 and p24 antibodies was not found in this study, the p40 ECLIA count in schizophrenia patients was higher than that of blood donors. Furthermore, we examined 90 sera from Japanese feral horses. Antibody profiles of control human samples are similar to that of naturally BDV-infected feral horses. We concluded that BDV infection was associated in some way with psychiatric disorders. | |
| 10229402 | Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 y | 1999 Apr | OBJECTIVE: (1) To review the diagnoses after 10 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD). (2) To examine the death rates and disease remissions in these patients. METHODS: This inception cohort of 410 patients had less than one year of signs and/or symptoms of CTD. Diagnoses of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and poly/dermatomyositis (PM/DM) were made in 197 patients using accepted diagnostic and classification criteria. Diagnoses of undifferentiated CTD were made in 213 patients. These latter patients were placed in 3 categories: isolated Raynaud's phenomenon (RP), unexplained polyarthritis (UPA), and undifferentiated CTD (UCTD), defined as meeting at least 3 of 11 specific manifestations of CTD. The diagnoses and remissions in all patients after 10 years were determined. RESULTS: Patients with well established CTD tended to remain with the original diagnosis. The 10 year survival was at least 87% in all diagnostic categories, with the exception of SSc, in which it was 56%. The progression of UPA to RA occurred infrequently. The presence of antinuclear antibodies suggested that UPA may develop additional symptoms and/or a specific diagnosis, and RP in these patients increased the likelihood of progressing to UCTD or a specific well established CTD. Ten percent of patients with RP progressed to SSc. In patients with UCTD, joint pain/tenderness and swelling counts were associated with progression to other diagnoses including RA, while either serositis, malar rash, or discoid lupus suggested the eventual diagnosis of SLE. CONCLUSION: The survival of patients with SSc was poor, with most dying early in the course of their disease. Remissions were seen in all groups of patients except SSc. The remissions were sometimes transient in SLE. Undifferentiated disease at initial examination within 12 months of onset usually remains undifferentiated. | |
| 9890974 | Identification of a cytokine-induced repressor of interleukin-1 stimulated expression of s | 1999 Jan 22 | Stromelysin 1 (MMP-3) is a matrix metalloproteinase with broad substrate specificity that has been linked to joint and tissue destruction associated with chronic inflammatory diseases such as rheumatoid arthritis and periodontitis. Transcription of the stromelysin gene is induced by inflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor as well as a number of other cytokines and mitogens, but the exact mechanisms involved in its regulation are not fully understood. To identify transcription factors and cis elements potentially involved in the IL-1 induction of stromelysin, the human stromelysin 5'-flanking region was screened by electrophoretic mobility shift assay for IL-1-induced DNA-binding complexes in human synovial and gingival fibroblasts. Here we report the identification of such a complex binding to the region -1614 to -1595 (5'-G(T)TTTTTCCCCCCATCAAAG-3') termed the stromelysin IL-1 responsive element site. Binding to this site is also induced by tumor necrosis factor but not by platelet-derived growth factor or interleukin 4. UV cross-linking demonstrates that there are at least two DNA-binding proteins involved, of approximately 48 and 52 kDa. Transient transfection experiments in human foreskin fibroblasts demonstrate that proteins binding to this site act as a repressor of IL-1-induced expression of the stromelysin gene. | |
| 9285244 | Selective immunomodulatory activity of SK&F 106615, a macrophage-targeting antiarthritic c | 1997 Aug | The azaspiranes are novel immunomodulators which are effective in a variety of animal models of autoimmune disease and transplantation. The compounds appear to target macrophages and alter their functional activity. One of these compounds, SK&F 106615 (N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride), is now in phase II clinical trials for rheumatoid arthritis. As many drugs/compounds effective in autoimmune disease and transplantation are overtly immunosuppressive, we designed studies to show that SK&F 106615 has selective immunomodulatory effects and that it does not perform in a manner characteristic of classical immunosuppressive agents on immune function. SK&F 106615 inhibited mouse and rat spleen cell and rat peripheral blood mononuclear cell proliferation in vitro with an IC50 of 500 nM. In vivo, treatment of C57BL/6 mice (15 mg/kg/day, i.p.) or rats (20 mg/kg/day, p.o.) for 2 weeks had no effects on specific antibody synthesis to ovalbumin (OVA) compared to rapamycin (RAP) which completely suppressed the antibody response. Compared to cyclosporin A (CsA), FK 506 and RAP which suppressed the antibody (plaque forming) response to particulate (sheep red blood cells) antigen in a dose responsive manner, SK&F 106615 administered at a dose of 50 mg/kg was inactive. There was an inhibition of the proliferative response of lymph node cells from treated mice and rats to mitogen and antigen in ex vivo assays. SK&F 106615, but not RAP, induced cells in the spleens of mice that could inhibit normal spleen cell proliferation in a co-culture assay. Thus, a selective immunomodulatory effect can be shown for SK&F 106615 in the absence of generalized immunosuppression. |