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ID PMID Title PublicationDate abstract
14995005 Factors associated with chloroquine-induced retinopathy in rheumatic diseases. 2004 Antimalarials are very useful drugs in the treatment of various rheumatic diseases. One of their main side effects is ocular toxicity, specifically retinopathy. Our objective was to identify risk factors associated with chloroquine retinopathy. A single, trained evaluator reviewed patient records with rheumatic diseases. They were taking chloroquine and identified by the ophthalmology department as having retinopathy during their routine eye evaluation. These cases were classified according to clinical evaluation, visual fields and fluorangiographic study. Up to four controls were selected for each case, matched by age, gender, diagnosis and similar time on chloroquine. In all, 34 variables were studied, among these: weight, age, disease duration, keratopathy, total cumulative dose (TCD), mean daily dose (MDD), lean body weight adjusted daily dose (LBWDD) and laboratory tests. Descriptive and inferential statistics comparing cases and controls in all patients and subgroup analysis were carried out. Significance was set at the 0.05 level. Odds ratio and 95% confidence intervals were calculated. Sixteen cases of chloroquine retinopathy were identified, eight patients with rheumatoid arthritis (RA), seven with systemic lupus erythematosus (SLE) and one with dermatomyositis. All were female. Mean age was 47.3 +/- 12.2 years; weight 59.5 +/- 10.7 kg; disease duration 12.8 +/- 6.0 years; time on chloroquine 54.1 +/- 27.8 (min-max: 30-197) months. There was a significant difference in the following variables in all patients: MDD 212.3 +/- 52.6 versus 170 +/- 51.3, p = 0.009; and LBWDD 5 +/- 1 versus 4.2 +/- 1.5, p = 0.03, for cases and controls, respectively. In subgroup analysis the MDD remained significantly different (235.5 +/- 45.8 versus 169.7 +/- 46.1, p = 0.004) only in RA, whereas LBWDD was different both in SLE and RA. Keratopathy increased the risk for retinopathy: OR, 95% CI: 5, 1.4-17.6, p = 0.01. In conclusion, in accordance with previous studies, the MDD, LBWDD and keratopathy were risk factors associated with chloroquine retinopathy. Periodic ophthalmologic evaluations are mandatory.
12945719 Therapy with statins in patients with refractory rheumatic diseases: a preliminary study. 2003 We have explored the therapeutic potential of statins in patients with different inflammatory rheumatic diseases refractory to conventional therapy. We found that simvastatin (80mg o.d. for eight days) induced a rapid and significant reduction in proteinuria levels in three systemic lupus erythematosus (SLE) patients. A similar kind of therapy had a marked beneficial effect in a patient with Wegener's granulomatosis and a patient with erythema nodosum. On the other hand, five patients with rheumatoid arthritis (RA) who received atorvastatin for eight days (20mg/day) showed reduction in C-reactive protein levels and a clinical improvement that was classified as an ACR20 response. Prior to the administration of statins, all these patients had received aggressive conventional therapy with no satisfactory response. A significant reduction in spontaneous apoptosis of peripheral blood lymphocytes and expression of CD69 and HLA-DR was observed in SLE patients after simvastatin therapy. These results prompted us to perform a pilot short-time comparative (simvastatin versus chloroquine) open clinical trial in 15 patients with RA who were receiving methotrexate as a single disease modifying antirheumatic drug with no satisfactory response. Most patients (9/10) who received simvastatin (40mg/day) showed an ACR50 or better response after eight weeks, whereas such a response was not observed in any patient (0/5) treated with chloroquine. Our preliminary results indicate that statins may be an important therapeutic tool for the treatment of inflammatory rheumatic diseases.
12934959 2 minute non-invasive screening for cardio-vascular diseases: relative limitation of C-Rea 2003 Contrary to the present practice of measurement of cardio-vascular risk factors or inflammatory risk factors such as C-Reactive Protein (CRP) from a blood sample from the vein of one arm, by using the Bi-Digital O-Ring Test Resonance Phenomena between 2 identical substances, one can non-invasively detect the approximate location on the body of abnormally increased risk factors in just 2 minutes, by detecting the resonance with L-Homocystine, even when blood CRP failed to detect any abnormality. This is performed by projecting a 0.5 to approximately 5mW red spectral laser beam with 560-670nm wavelength, to at least 6 standard parts of the body, when one of the control risk markers placed next to the laser beam also exists in the part of the body tested. It is generally believed that CRP is increased in the presence of acute myocardial infarct, chronic rheumatoid arthritis, ulcerative colitis, metabolic abnormalities such as often detected in diabetes, inflammation and underlying infection of the cardio-vascular system, and in some cancers. However, in our study, when the clinical significance of CRP and L-Homocystine was compared, we found that CRP often was not increased when there was extensive infection of Mycobacterium Tuberculosis as well as asymptomatic infection by Cytomegalovirus, Herpes Simplex Virus Type I, Human Herpes Virus Type 6, Borrelia Burgdorferi, or Chlamydia Trachomatis in the heart (and other parts of the body), particularly when there was liver cell dysfunction such as an increase in ALT. In contrast, L-Homocystine was often increased in the presence of localized infections of the heart and other parts of the body. For screening of Cardio-Vascular diseases by this method, 0.5mg of L-Homocystine as a control marker was found to be the most sensitive and reliable, compared with most effective amount of CRP, 0.5ng, for detecting early Cardio-Vascular problems due to various localized infections. About 0.5ng of cardiac Troponin T and cardiac Troponin I were also useful for detecting early stages of heart disease but they are not as sensitive as L-Homocystine. Once the pathogenic factors were identified, the effective medication was given, and the Selective Drug Uptake Enhancement Method (originally discovered by the first author in 1990) was applied after the effective drug was administered, to selectively deliver the medication to the pathological area, while reducing drug uptake to the normal parts of the body. As a result, the therapeutic effect was markedly accelerated.
12899549 Costs of internal fixation and arthroplasty for displaced femoral neck fractures: a random 2003 Jun We included in a prospective, randomized study 68 patients aged 70 years or older, with displaced cervical hip fractures. The patients were randomized to internal fixation with hook-pins (36) or primary arthroplasty (32) (total or hemiarthroplasty due to their prefracture status) and followed for 2 years. Patients with rheumatoid arthritis, mental confusion and/or residence in an institution were excluded. The postoperative stay in hospital, rehabilitation wards or nursing homes were recorded as well as complications and the costs of surgery. The aim of this study was to compare the accumulated costs of each method, during the first 2 years after the fracture. In the internal fixation group, 15/36 were considered failures, as compared to 1/32 in the arthroplasty group. As regards primary treatment of the fracture, the durations of surgery and hospital stay were shorter after internal fixation, but the total need for hospitalization/institutionalization was somewhat longer in these patients. The mean 2-year cost for a patient with internal fixation was USD 21,000 and of one with primary arthroplasty USD 15,000. We conclude that primary arthroplasty is a cost-efficient treatment. Considering the very much higher failure rate after internal fixation--leading to increased suffering for these patients--primary arthroplasty stands out as the best method for displaced fractures of the femoral neck.
12860579 Causes of death in patients with celiac disease in a population-based Swedish cohort. 2003 Jul 14 BACKGROUND: Patients with celiac disease have an increased risk of death from gastrointestinal malignancies and lymphomas, but little is known about mortality from other causes and few studies have assessed long-term outcomes. METHODS: Nationwide data on 10 032 Swedish patients hospitalized from January 1, 1964, through December 31, 1993, with celiac disease and surviving at least 12 months were linked with the national mortality register. Mortality risks were computed as standardized mortality ratios (SMRs), comparing mortality rates of patients with celiac disease with rates in the general Swedish population. RESULTS: A total of 828 patients with celiac disease died during the follow-up period (1965-1994). For all causes of death combined, mortality risks were significantly elevated: 2.0-fold (95% confidence interval [CI], 1.8-2.1) among all patients with celiac disease and 1.4-fold (95% CI, 1.2-1.6) among patients with celiac disease with no other discharge diagnoses at initial hospitalization. The overall SMR did not differ by sex or calendar year of initial hospitalization, whereas mortality risk in patients hospitalized with celiac disease before the age of 2 years was significantly lower by 60% (95% CI, 0.2-0.8) compared with the same age group of the general population. Mortality risks were elevated for a wide array of diseases, including non-Hodgkin lymphoma (SMR, 11.4), cancer of the small intestine (SMR, 17.3), autoimmune diseases (including rheumatoid arthritis [SMR, 7.3] and diffuse diseases of connective tissue [SMR, 17.0]), allergic disorders (such as asthma [SMR, 2.8]), inflammatory bowel diseases (including ulcerative colitis and Crohn disease [SMR, 70.9]), diabetes mellitus (SMR, 3.0), disorders of immune deficiency (SMR, 20.9), tuberculosis (SMR, 5.9), pneumonia (SMR, 2.9), and nephritis (SMR, 5.4). CONCLUSION: The elevated mortality risk for all causes of death combined reflected, for the most part, disorders characterized by immune dysfunction.
12797547 The cox-2-specific inhibitor celecoxib inhibits adenylyl cyclase. 2003 Apr Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known causes of acute renal insufficiency and gastropathy in patients with chronic inflammatory diseases. This action is presumed to result from nonselective inhibition of both constitutive and inducible forms of prostaglandin H synthases, also known as the cyclooxygenase enzymes (i.e., COX-1 amd COX-2). Celecoxib (Celebrex) is a COX-2 enzyme inhibitor and has emerged as a preferred therapeutic agent for the treatment of rheumatoid arthritis as compared to other NSAIDs. Celecoxib has recently been the subject of criticism for its side effects, mainly arterial thrombosis and renal hemorrhage, although it is considered a superior drug in protecting the gastrointestinal tract. In the present study, we report that celecoxib not only inhibited COX-2, but also exhibited the property of inhibiting adenylyl cyclase, an important enzyme forming the intracellular second messenger 3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Celecoxib also inhibited cholera toxin-stimulated cAMP formation, which indicated its ability to permeate cell membranes in order to reach intracellular adenylyl cyclase. It inhibited in vitro adenylyl cyclase activity in both human colonic epithelial cells and purified adenylyl cyclase from Bordetella pertussis. The IC50 of celecoxib for B. pertussis adenylyl cyclase was calculated to be 0.375 mM. Lineweaver-Burk analysis showed that the type of enzyme inhibition was competitive. The apparent Km and Vm of adenylyl cyclase was calculated as 25.0 nM and 7.14 nmol/min/mg, respectively. Celecoxib changed the Km value to 66.6 nM without affecting the Vmax. The current study suggests that apart from inflammation, celecoxib therapy could be further extended to diseases involving cAMP upregulation either by endogenous reactions or exogenous agents. These new data showing inhibition of adenylyl cyclase should be considered in light of the drug's pathological effects or in patients specifically excluded from treatment (e.g., asthmatics).
12642763 C1-C2 posterior fusion in growing patients: long-term follow-up. 2003 Mar 15 STUDY DESIGN: A retrospective review of patients undergoing C1-C2 posterior fusion during childhood was undertaken. OBJECTIVES: The aim of this study was to investigate the change in the sagittal curvature of the cervical spine in children after C1-C2 posterior fusion. SUMMARY OF BACKGROUND DATA: There have been only a few reports on postoperative changes in the sagittal curvature of the cervical spine after C1-C2 posterior fusion in children. However, they have all described the onset of sagittal postoperative cervical deformities. METHODS: Between January 1977 and December 1992, a total of 12 children underwent C1-C2 posterior fusion for atlantoaxial instability resulting from congenital malformation in eight, juvenile rheumatoid arthritis in one, and rotatory subluxation in three. The average age at the time of surgery was 10.9 years (range 7-12 years). All children underwent a similar treatment program with gradual preoperative reduction in halo cast, followed by C1-C2 posterior fusion with Mersilene loops in two cases, wiring in eight (Gallie's or Brooks' techniques), and interlaminar clamps in the remaining two. The halo cast made it possible to avoid a hyperextended or hyperflexed C1-C2 position while performing the atlantoaxial fusion, thus ensuring a more anatomic position during C1-C2 fusion. In the postoperative period, the halo cast was maintained for 7 to 9 weeks. RESULTS Follow-up ranged from 7 years to 13 years. Preoperative alignment of the cervical spine was classified into two groups: lordosis (eight patients) and straight (four patients). Postoperative subaxial malalignment (kyphosis) occurred in four cases (33%): these patients showed evidence of spontaneous and gradual sagittal improvement and presented either a straight (two cases) or a lordotic (two cases) cervical spine at follow-up. Immediately after surgery, the cervical spine was normally aligned in the remaining eight patients (lordosis and straight alignment in six and two cases, respectively) and was unchanged at follow-up. At follow-up, none of the 12 patients had a cervical deformity on sagittal plane. CONCLUSION: In children, a spontaneous realignment of the subaxial kyphosis observed after C1-C2 posterior fusion can be noted at follow-up, when a postoperative deformity occurs (33% in the present series). According to the present findings, it is not always mandatory to perform occipitocervical fusion in children with atlantoaxial instability just to prevent subaxial deformity in the cervical spine.
12595626 Urinary levels of creatine and other metabolites in the assessment of polymyositis and der 2003 Feb BACKGROUND: A simple and reliable method is needed to assess disease activity and monitor the efficacy of therapy in polymyositis (PM) and dermatomyositis (DM). This study used in vitro proton ((1)H) magnetic resonance spectroscopy (MRS) to explore whether excretion of urinary metabolites can be used as a reliable marker of disease in PM and DM patients. METHODS: Urine samples were obtained from PM/DM patients (n=34), healthy controls (50) and subjects with known muscle-wasting conditions including adult-onset muscular dystrophy (8), stroke patients (10), rheumatoid arthritis (RA) patients on steroids (13) and not on steroids (16) and patients with alcoholic myopathy (12). Levels of urinary metabolites were then correlated with creatine kinase (CK) activities and quadriceps muscle strength. RESULTS: Creatine was detected in the urine in 26 of 35 patients with PM/DM, four of 60 cases with other medical disorders (including one with adult-onset dystrophy, one with a stroke and two with RA who were not on steroids) and 10 of 50 healthy controls. The urinary creatine/creatinine ratio exceeded 0.4 in 20 patients with PM/DM but no patients with other medical disorders and no healthy controls. These differences were highly significant (P<0.001) by Kruskal-Wallis test (comparing all groups) and by Mann-Whitney U-tests (comparing individual groups with PM/DM cases). Citrate, glycine, choline-containing compounds and taurine levels were significantly increased in PM/DM when compared with controls. There were positive correlations between CK activities and choline-containing compounds (r=0.78, P=0.0006) and also between CK activities and betaine (r=0.57, P=0.026). CONCLUSIONS: This study shows significant differences in the urinary levels of creatine, choline-containing metabolites, betaine and citrate in PM/DM subjects compared with controls, although further work is required to elucidate the underlying metabolic processes.
12587686 Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion 2002 Dec There is preliminary clinical evidence to support the contention that the anti-inflammatory and analgesic properties of bromelain help to reduce symptoms of osteo- and rheumatoid arthritis. However, there have been no controlled studies of its effects on joint health in healthy subjects who lack such diagnosis. The current study investigated the effects of bromelain on mild acute knee pain of less than 3 months duration in otherwise healthy adults. The study was an open, dose-ranging postal study in volunteers who had been recruited through newspaper and magazine articles. Two validated questionnaires (WOMAC knee health Index and the Psychological Well-Being Index) were completed at baseline and after one month's intervention with bromelain, randomly allocated to volunteers as either 200 mg or 400 mg per day. Seventy seven subjects completed the study. In both treatment groups, all WOMAC symptom dimension scores were significantly reduced compared with baseline, with reductions in the final battery (total symptom score) of 41 and 59% (P = 0.0001 and <0.0001) in the low and high dose groups respectively. In addition, improvements in total symptom score (P = 0.036) and the stiffness (P = 0.026) and physical function (P = 0.021) dimensions were significantly greater in the high-dose (400 mg per day) compared with the low-dose group. Compared to baseline, overall psychological well-being was significantly improved in both groups after treatment (P = 0.015 and P = 0.0003 in the low and high dose groups respectively), and again, a significant dose-response relationship was observed. We conclude that bromelain may be effective in ameliorating physical symptoms and improving general well-being in otherwise healthy adults suffering from mild knee pain in a dose-dependant manner. Double blind, placebo-controlled studies are now warranted to confirm these results.
12510088 [Total knee arthroplasty: a 4.5-year follow-up]. 2002 OBJECTIVES: To present the short- and mid-term follow-up results of primary total knee arthroplasty. METHODS: We performed a total of 97 cemented total knee replacements (47 right, 50 left) with posterior cruciate ligament retention in 66 patients (60 women, 6 men). The mean age at the time of surgery was 65.2 years (range 29 to 82 years). Preoperative diagnoses were primary osteoarthrosis (n=60), rheumatoid arthritis (n=3), systemic lupus erythematosus (n=2), and post-traumatic osteoarthritis (n=1). Thirty-one patients had bilateral knee replacements, of which 29 were performed at the same session. Pre- and postoperative clinical evaluations were made according to the clinical rating system of the Knee Society. Radiographic evaluations were made according to the Fairbank's criteria preoperatively, and to the total knee arthroplasty radiographic evaluation and scoring system of the Knee Society postoperatively. The mean follow-up was 4.5 years (range 24 to 98 months). RESULTS: Clinical results were good or excellent in 94.8 percent of patients. Complications encountered were deep infection in two patients, patellar dislocation in two patients, deep venous thrombosis in two patients, and patellar tendon rupture in one patient. The mean increases in knee and functional scores were 42.94 and 39.87, respectively. Improvement in the mean postoperative knee flexion was 35.72 degrees. The mean leg alignment was 6.3 degrees valgus. No components required revision because of aseptic loosening. CONCLUSION: Posterior cruciate ligament retaining implants were found to yield successful clinical and radiologic results during short- and mid-term follow-up period.
12502363 Synthetic analogues of the bacterial signal (quorum sensing) molecule N-(3-oxododecanoyl)- 2003 Jan 2 Comparative immune modulatory activity for a range of synthetic analogues of a Pseudomonas aeruginosa signal molecule, N-(3-oxododecanoyl)-l-homoserine lactone (3O, C(12)-HSL), is described. Twenty-four single or combination systematic alterations of the structural components of 3O, C(12)-HSL were introduced as described. Given the already defined immunological profile of the parent compound, 3O, C(12)-HSL, these compounds were assayed for their ability to inhibit murine and human leucocyte proliferation and TNF-alpha secretion by lipopolysaccharide (LPS) stimulated human leucocytes in order to provide an initial structure-activity profile. From IC(50) values obtained with a murine splenocyte proliferation assay, it is apparent that acylated l-homoserine lactones with an 11-13 C side chain containing either a 3-oxo or a 3-hydroxy group are optimal structures for immune suppressive activity. These derivatives of 3O, C(12)-HSL with monounsaturation and/or a terminal nonpolar substituent on the side chain were also potent immune suppressive agents. However, structures lacking the homoserine lactone ring, structures lacking the l-configuration at the chiral center, and those with polar substituents were essentially devoid of activity. The ability of compounds selected from the optimal activity range to modulate mitogen-driven human peripheral blood mononuclear cell proliferation and LPS-induced TNF-alpha secretion indicates the suitability of these compounds for further investigation in relation to their molecular mechanisms of action in TNF-alpha driven immunological diseases, particularly autoimmune diseases such as psoriasis, rheumatoid arthritis, and type 1 (autoimmune) diabetes.
12414758 Streptokinase promotes development of dipeptidyl peptidase IV (CD26) autoantibodies after 2002 Nov Dipeptidyl peptidase IV (DPP IV) (CD26) plays a critical role in the modulation and expression of autoimmune and inflammatory diseases. We recently reported that sera from patients with rheumatoid arthritis and systemic lupus erythematosus contained low levels of DPP IV and high titers of anti-DPP IV autoantibodies of the immunoglobulin A (IgA) and IgG classes and found a correlation between the low circulating levels of DPP IV and the high titers of anti-DPP IV autoantibodies of the IgA class. Since streptokinase (SK) is a potent immunogen and binds to DPP IV, we speculated that patients with autoimmune diseases showed higher DPP IV autoantibody levels than healthy controls as a consequence of an abnormal immune stimulation triggered by SK released during streptococcal infections. We assessed this hypothesis in a group of patients suffering from acute myocardial infarction, without a chronic autoimmune disease, who received SK as part of therapeutic thrombolysis. Concomitant with the appearance of anti-SK antibodies, these patients developed anti-DPP IV autoantibodies. These autoantibodies bind to DPP IV in the region which is also recognized by SK, suggesting that an SK-induced immune response is responsible for the appearance of DPP IV autoantibodies. Furthermore, we determined a correlation between high titers of DPP IV autoantibodies and an augmented clearance of the enzyme from the circulation. Serum levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) increased significantly after 30 days of SK administration, while the levels of soluble IL-2 receptor remained unchanged during the same period, suggesting a correlation between the lower levels of circulating DPP IV and higher levels of TNF-alpha and IL-6 in serum in these patients.
12351553 High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome a 2002 Oct BACKGROUND: Women with endometriosis may also have associated disorders related to autoimmune dysregulation or pain. This study examined whether the prevalence of autoimmune, chronic pain and fatigue and atopic disorders is higher in women with endometriosis than in the general female population. METHODS AND RESULTS: A cross-sectional survey was conducted in 1998 by the Endometriosis Association of 3680 USA members with surgically diagnosed endometriosis. Almost all responders had pain (99%), and many reported infertility (41%). Compared with published rates in the general USA female population, women with endometriosis had higher rates of hypothyroidism (9.6 versus 1.5%, P < 0.0001), fibromyalgia (5.9 versus 3.4%, P < 0.0001), chronic fatigue syndrome (4.6 versus 0.03%, P < 0.0001), rheumatoid arthritis (1.8 versus 1.2%, P = 0.001), systemic lupus erythematosus (0.8 versus 0.04%, P < 0.0001), Sjögren's syndrome (0.6 versus 0.03%, P < 0.0001) and multiple sclerosis (0.5 versus 0.07%, P < 0.0001), but not hyperthyroidism or diabetes. Allergies and asthma were more common among women with endometriosis alone (61%, P < 0.001 and 12%, P < 0.001 respectively) and highest in those with fibromyalgia or chronic fatigue syndrome (88%, P < 0.001 and 25%, P < 0.001 respectively) than in the USA female population (18%, P < 0.001 and 5%, P < 0.001 respectively). CONCLUSIONS: Hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthma are all significantly more common in women with endometriosis than in women in the general USA population.
12237255 Pharmacological analysis for mechanisms of GPI-80 release from tumour necrosis factor-alph 2002 Oct 1 GPI-80, a glycosylphosphatidylinositol (GPI)-anchored protein initially identified on human neutrophils, plays a role(s) in the regulation of beta2 integrin function. Previous studies have shown that GPI-80 is sublocated in secretory vesicles. It is also found in soluble form in the synovial fluid of rheumatoid arthritis patients, and in the culture supernatant of formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils. To understand the behaviour of GPI-80 under conditions of stimulation, we investigated the effects of tumour necrosis factor (TNF)-alpha on its expression and release. We also probed the mechanism of its release with various pharmacologic tools. 2 TNF-alpha induced the release of GPI-80 from human neutrophils in a concentration- and time-dependent manner (in the range of 1-100 u ml(-1) and 30-120 min, respectively), but did not affect surface GPI-80 levels. 3 Cytochalasin B, genistein, and SB203580 but not PD98059 inhibited TNF-alpha-stimulated GPI-80 release and neutrophil adherence at the same concentration. In addition, TNF-alpha-induced GPI-80 release was inhibited by blocking monoclonal antibodies specific to components of Mac-1 (CD11b and CD18). 4 Antioxidants (pyrrolidine dithiocarbamate and N-acetyl-L-cysteine) inhibited GPI-80 release by TNF-alpha stimulation, but superoxide dismutase did not. Antioxidants but not superoxide dismutase reduced an intracellular oxidation state. 5 These findings indicate that TNF-alpha-stimulated GPI-80 release from human neutrophils depends upon adherence via beta2 integrins. They also suggest that cytochalasin B, genistein, and SB203580 inhibit GPI-80 release by suppressing signals for cell adherence, rather than by a direct effect on its secretion. Finally, we suggest that GPI-80 release involves an intracellular change in a redox state.
12148596 Serum sFAS levels are elevated in ANCA-positive vasculitis compared with other autoimmune 2002 Jul The role of the Fas/FasL system in ANCA-associated vasculitis is unclear. We therefore assessed levels of soluble Fas (sFas) in sera and Fas expression on mononuclear cells from patients with ANCA-positive vasculitis and compared the results with those found in other rheumatic diseases. Serum levels of sFas were determined by ELISA. The ANCA-positive vasculitis patients studied included 29 at onset, 17 in first remission while on therapy, and 12 in quiescence. For comparison, 10 patients with Sjogren's syndrome (SS), 14 patients with systemic lupus erythematosus (SLE), 29 patients with rheumatoid arthritis (RA), 7 patients on dialysis (DP), and 26 healthy controls (HC) were studied. In addition, Fas expression in mononuclear cells was examined at the mRNA level using reverse transcriptase (RT)-PCR in 6 vasculitis patients at onset and in first remission. The expression of CD95 on the surface of leukocytes was determined by flow cytometry in 6 vasculitis patients at onset of the disease, in 6 patients in clinical remission, and in 6 HC. Expression of Fas and FasL in renal biopsy specimens was studied using immunohistochemistry. Patients with vasculitis had high sFas levels irrespective of disease phase. Both vasculitis patients and patients with RA and SLE had significantly increased sFas levels compared with healthy controls. All patient groups had sFas levels, which correlated with raised serum creatinine values. However, the sFas levels in vasculitis patients in first remission and in quiescence were increased despite a lower serum creatinine compared with onset. Some of the vasculitis patients showed an increased mRNA expression of Fas in mononuclear cells after treatment, suggesting that Fas production fluctuates with the intensity of the disease. The expression of CD95 on leukocytes was slightly decreased in vasculitis patients compared to healthy controls. No alterations of Fas and FasL expression were seen in renal biopsy specimens. These results show that ANCA-positive vasculitis patients have high sFas levels and that the levels remain elevated even in clinical remission. The findings indicate that perturbations in the Fas/Fas ligand system may play a role in the disease process in ANCA vasculitis.
11875502 Autoantigen microarrays for multiplex characterization of autoantibody responses. 2002 Mar We constructed miniaturized autoantigen arrays to perform large-scale multiplex characterization of autoantibody responses directed against structurally diverse autoantigens, using submicroliter quantities of clinical samples. Autoantigen microarrays were produced by attaching hundreds of proteins, peptides and other biomolecules to the surface of derivatized glass slides using a robotic arrayer. Arrays were incubated with patient serum, and spectrally resolvable fluorescent labels were used to detect autoantibody binding to specific autoantigens on the array. We describe and characterize arrays containing the major autoantigens in eight distinct human autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. This represents the first report of application of such technology to multiple human disease sera, and will enable validated detection of antibodies recognizing autoantigens including proteins, peptides, enzyme complexes, ribonucleoprotein complexes, DNA and post-translationally modified antigens. Autoantigen microarrays represent a powerful tool to study the specificity and pathogenesis of autoantibody responses, and to identify and define relevant autoantigens in human autoimmune diseases.
11813159 Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-alpha 2002 Feb Leukocyte extravasation into tissues is a multi-step process culminating in the migration of cells through the basement membrane. This requires the production of matrix-degrading enzymes, in particular matrix metalloproteinases (MMP). We investigated the role of chemokines in regulating MMP production in the monocytic cell line THP-1 and in peripheral blood monocytes (PBM). The CC chemokines CCL2 (MCP-1), CCL3 (MIP-1alpha), and CCL5 (RANTES) stimulated the release of monocyte MMP-9 protein in a bell-shaped dose-dependent manner. The increase in MMP-9 protein detected at 24 h was due to de novo synthesis, confirmed by Northern blotting, with MMP-9 mRNA detectable at 6-8 h. Autocrine TNF-alpha was necessary for chemokine stimulation of MMP-9. Chemokines increased TNF-alpha mRNA levels and protein release in monocytes and THP-1 cells, and neutralizing anti-TNF-alpha antibodies inhibited CCL2-induced MMP-9 release. Furthermore, the broad spectrum MMP inhibitor BB 2516, which inhibits TNF-alpha release, abrogated CCL2- and CCL5-induced MMP-9 release in both THP-1 cells and freshly isolated monocytes. Monocyte production of MMP is of major importance in the pathology of cancer, asthma, and rheumatoid arthritis. An understanding of the mechanisms by which these MMP are produced may lead to novel therapies to modulate extravasation of leukocytes in disease.
11802309 n-3 fatty acids and the immune system in autoimmunity. 2002 Jan In short-term studies, both in animals and in humans, fish oil seems to exert anti-inflammatory effects. However, these effects may vanish during long-term treatment. There is a possibility that in autoimmune diseases, supplementation of dietary n-3 fatty acids might lead to a decrease in the number of autoreactive T cells via apoptosis, as demonstrated in (NZBXNZW) F1 lupus mice [40]. Thus, the "fade away" effect might be due to regrowth of pathogenic autoreactive cells. In animal models of autoimmune diseases, diets high in n-3 fatty acids from fish oil increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, while n-6 linoleic acid-rich diets appear to increase disease severity. The situation in human disease is probably more complex. Some of the discrepancy between studies can be attributed to methodologic problems. The effect of fish oil is dose, time and disease-dependent. Since the anti-inflammatory effects depend on the balance between n-3 and n-6 fatty acids, the relative proportion of EPA and DHA and possibly co-treatment with dietary vitamin E, the dose/effect ratio may vary between individuals. Furthermore, some animal studies demonstrating efficacy used very high doses that may be incompatible with human consumption. It seems that fish oil is only mildly effective in acute inflammation. In those chronic inflammatory disorders where it was found to be effective, several weeks are necessary to exhibit results. Yet, this mild anti-inflammatory effect, possibly through downregulation of pro-inflammatory cytokine production, leads to striking therapeutic improvement in critically ill patients. Fish oil supplementation seems advantageous especially in acute and chronic disorders where inappropriate activation of the immune system occurs. Fish oil has only a mild effect on active inflammation of diseases such as rheumatoid arthritis, SLE and Crohn's disease, but it could prevent relapse (in some of the studies). In diseases where the inflammation is mild, such as IgA nephropathy, fish oil may slow or even prevent disease progression. The above could explain the observation in some populations of a decreased incidence of inflammatory and autoimmune diseases [3], since the constant consumption of n-3 fatty acids could suppress any autoreactive (or hyper-reactive) T cells. However, if there is already an existing disease, increased consumption might not be beneficial over a long period. Therefore, the use of n-3 fatty acids can be recommended to the general healthy population, not only to prevent atherosclerosis but possibly also to reduce the risk of autoimmunity.
11772593 Efficacy and safety of chlorambucil in intractable noninfectious uveitis: the Massachusett 2002 Jan PURPOSE: To report our experience with the use of chlorambucil for otherwise treatment-resistant uveitis and to assess its safety and efficacy. DESIGN: Noncomparative interventional case series. PARTICIPANTS: Twenty-eight patients with intractable noninfectious uveitis. METHODS: We reviewed the records of 28 patients (56 eyes) with chronic noninfectious uveitis who were treated with chlorambucil from 1987 to 2000. Diagnoses included Adamantiades-Behçet's disease (ABD) (7 patients), juvenile rheumatoid arthritis (JRA)-associated uveitis (10 patients), pars planitis (2 patients), sympathetic ophthalmia (1 patient), idiopathic uveitis (6 patients), Crohn's disease (1 patient), and HLA-B27-associated uveitis (1 patient). All patients were refractory to other immunomodulatory therapy and systemic steroids. The median duration of treatment with chlorambucil was 12 months (range, 4-50 months), whereas the median daily dosage was 8 mg (range, 4-22 mg). Patients were followed for a median follow-up period of 46 months (range, 4-166 months) after chlorambucil treatment was begun and continued to be followed for relapse after cessation of therapy. MAIN OUTCOME MEASURES: Visual outcome, response to treatment, treatment-related side effects, drug dosage, previous and final treatment, discontinuation of systemic corticosteroids. RESULTS: Chlorambucil was discontinued in seven patients because of side effects: two females had temporary amenorrhea develop, two patients had unacceptable gastrointestinal intolerance, one patient had infection, and 2 patients had progressive leukopenia. Nineteen patients (68%) showed positive clinical response to the treatment, four (14%) initially responded then relapsed after discontinuation of the drug, three patients with ABD had improvement of ocular disease but worsening of systemic symptoms, and two had persistent inflammation. Visual acuity was improved in 24 eyes (43%), stable in 22 (39%), and worsened in 10 eyes (18%). Systemic prednisone was successfully discontinued in 19 of the 28 patients (68%), and 14 patients were free of inflammation at the end of follow-up without any systemic medication. CONCLUSIONS: Chlorambucil can be a safe and effective alternative for preserving vision in patients with otherwise treatment resistant uveitis.
15686636 [Total knee arthroplasty with the Beznoska S.V.L. implant: short-term results]. 2004 PURPOSE OF THE STUDY: To present and evaluate short-term clinical results of total knee arthroplasty using the Beznoska S. V. L. implant and to compare them with the results of other authors. MATERIAL: In the period from April 1997 to October 2002, 197 total knee replacements with a S. V. L. implant were carried out of these, 164 implants were evaluated in 146 patients. This group comprised 116 women (78 %) and 48 men (22 %), with an average age of 73.6 years (range, 63 to 83) at the time of surgery. The patients were evaluated on average at 4.3 years (range, 1.5 to 6.5) after surgery. Indications for replacement were primary knee arthritis in 151, rheumatoid arthritis in nine, secondary post-traumatic arthritis in two and conditions following tibial osteotomy in two cases. METHODS: The results were evaluated using the Knee Society Clinical Rating System which consists of three parts: Knee Score (100 points), Knee Function Score (100 points) and Categorical Score (allocating patients to three groups according to function deficiencies of other joints). X-ray images were examined for implant position, the presence of radiolucent lines and patellar position, and assessed on the basis of the Knee Society Total Knee Arthroplasty Roentgenographic and Scoring System. RESULTS: No or mild pain in the treated joint was reported by 90.2 % of the patients. Severe pain was not recorded at all. The average maximal range of flexion increased from 94 degrees preoperatively to 104 degrees post-operatively. The range of motion more than 90 degrees and that of more than 100 degrees were recorded in 96 % and 76.8 % of the operated-on knees, respectively. An anteroposterior mild instability of 5 to 10 mm was objectively found in nine knees (5.5 %) a medial laxity of 6 to 9 degrees was detected in 36 knees (22 %) and that of 10 to 15 degrees only in one patient. Severe instability was not recorded. The leg axis achieved after surgery was on average 6.4 degrees valgus, compared to 5.5 degrees varus before surgery. The total Knee Score was 85.1 points (range, 53 to 100), with excellent or good outcomes in 151 knee replacements (92 %). Six patients (4.6 %) reported failure to walk a distance of more than 500 m on an even terrain, six (4.6 %) could not manage the stairs and five (3 %) required a permanent use of two crutches or a walking frame. The average function score, which also included the effect of concomitant diseases of other joints, was 64.9 points (range, 40 to 100), with excellent or very good outcomes being achieved in 64 implants (39 %). On X-ray examination of implant position in anteroposterior projection, the average valgus angle of the femoral component was 94.8 degrees (range, 92 to 100) and the tibial angle was 90.3 degrees (range, 85 to 94). In lateral projection the flexion angle of the femoral component was 2.5 degrees (-1 to 6) and the average dorsal tilt of the tibia was 3 degrees. Distinct radiolucent lines up to 1 mm in width were seen in the femoral component in 10 (6 %) cases and in the tibial component in 27 (16.5 %) cases, this occurred in zones 1, 2 or 4. Wider lines of 2 mm were present in both components in 6 (3 %) cases. Radiolucent lines were recorded in 43 (26 %) implants. The patella examined in axial projection was correctly centered in 140 (85 %) total knee replacements. Eleven patients reported femoropatellar problems and, in three of them, patella replacement was subsequently performed. No aseptic loosening occurred and one deep infection (0.6 %) was treated by a two-stage reimplantation. DISCUSSION: Excellent to very good outcomes, with an average Knee Score of 85.1 points, were achieved in 92 % of the implants. The total outcome characterized by an average Functional Score of 64.9 points was related to a higher average age of our patients and a high proportion of patients with diseases of other joints, which interfered with overall mobility and self-sufficiency. The results of implant position evaluation, based on X-ray examination, showed good values, which testifies to the use of an appropriate surgical technique and accuracy of the instrumentation applied. The occurrence of radiolucent lines was low, as was the number of complications. Our results are comparable with those reported in the literature. CONCLUSIONS: Our short-term evaluation shows that the S. V. L. implant is fully useful for total knee replacement in patients of higher age categories.