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ID PMID Title PublicationDate abstract
9150114 Pre-existing autoimmune disease in patients with long-term survival after allogeneic bone 1997 May We reviewed the experience with allogeneic bone marrow transplantation (BMT) at Fred Hutchinson Cancer Research Center and affiliated Seattle hospitals for patients with preexisting autoimmune diseases. The review was limited to patients who received transplants between 1969 and 1989 from a related donor and who had at least 3 years of relapse-free survival. Of 901 evaluable patients, 11 were identified with a preexisting autoimmune disease and 2 with diseases that were possibly autoimmune in nature. Pretransplant diseases identified in this review included rheumatoid arthritis (n = 1), discoid or systemic lupus (n = 2), insulin dependent Type 1 diabetes (n = 3), hyperthyroidism (n = 4), dermatitis herpetiformis (n = 1), vasculitis (n = 1), and Crohn's disease (n = 1). All 13 patients survive with a median followup of 14 (range, 7-20) years after transplantation from an HLA identical sibling (n = 10), parent (n = 1) or identical twin (n = 2). Pre and post-transplant histories are presented. Variables to be considered in the assessment of any beneficial effect of BMT are discussed, including consideration of different patterns of activity that describe the natural history of various autoimmune diseases. Although autoimmune disease did not recur after allogeneic BMT in these 13 patients, disease and post-transplant variables may confound the interpretation of results from retrospective analysis.
12012569 [Fatty acids of the tuna of different fishing areas of the Mexican Pacific, canned in oil 2001 Dec A direct relationship exists between the state of health and the diet, and inside this some components, such as the fatty acids (FA), influence mostly in the prevention of certain illnesses (coronary heart disease, hypertension, rheumatoid arthritis, inflammatory answer, and arterial pressure). One of the main sources of essential FA are the marine products; the tuna is a marine food of wide consumption in Mexico due its readiness and low cost. The objective of this work was to determine the profile of fatty acids (FA) in tuna canned in oil and in water coming from three fishing areas of the Mexican Pacific. There were randomly obtained 7 oil-tuna commercial marks (AA) and 5 water- tuna (AW) coming from the next fishery areas: Baja California Sur (L1), Colima (L2) and Mazatlán (L3). The samples without draining were liquefied and thereafter it was obtained the methyl esters of fatty acids that were analyzed by gas chromatography with a flame ionization detector. In all the areas were identified 20 FA (mg/100 g); three AG omega 3 (EPA, DHA and linolenic) and two omega 6 (linoleic and arachidonic). In the AA of the three areas the most abundant saturated FA were estearric and palmitic acids, the most abundant monounsaturated fatty acid was the cis-vaccenic, followed by the oleic acid. The behavior of those omega 3 in the AA of the three areas were similar: with the less quantity was the linolenic acid (447-755), continued by the EPA (979-1323) and finally high concentrations of DHA (1862-3327). In the AW the DHA was the most abundant fatty acid in all the areas (1086-4456), the most abundant monounsaturated fatty acid was the palmitic (640-3809). It was observed the presence of trans fatty acids in high quantities in AW: linolelaidic (1394-1495) and elaidic (377-1234). The relationship omega 3/omega 6 in the AA was similar in L1 and L2, and lower in L3; in AW was higher in L2 and L3. In conclusion, evident variation exists in the content of FA among areas; it could be considered that the AA of L3 and AW of L2 as the richest in omega-3 and omega-6 FA. In general, the tuna in water is a richer food in FA omega 3 and omega 6 that the tuna in oil, independently of the fishery area.
11786679 Growth hormone therapy in the glucocorticosteroid-dependent child: metabolic and linear gr 2001 Pharmacological doses of glucocorticosteroids given chronically are associated with a variety of negative side effects which impact the prolonged use of these potent anti-inflammatory agents. They have catabolic effects on protein, resulting in poor tissue healing, an increased incidence of infections and accelerated bone loss. Insulin resistance to both hepatic and peripheral tissues is a common consequence of chronic steroid use, leading at times to impaired carbohydrate metabolism. Steroids affect both the release and the effects of growth hormone (GH) at the target sites, hence becoming functional GH antagonists. When administered to growing children the side effects of glucocorticosteroid treatment are further compounded by a potent and significant suppression of linear growth. Ample experimental and clinical data support a role for GH therapy in counteracting some of the effects of glucocorticosteroids. Using isotope dilution methods we have previously shown that both GH and insulin-like growth factor (IGF)-I can decrease the protein wasting effects of prednisone administration in man. IGF-I has also been shown to enhance type I collagen formation in hydrocortisone-treated human osteoblasts. GH (through IGF-I) significantly enhances linear growth; thus, in states of "functional" GH deficiency, such as that observed in chronic steroid use, GH may also have a potentially beneficial effect. Studies in children on chronic prednisone doses with cystic fibrosis, chronic renal failure or juvenile rheumatoid arthritis have all shown beneficial effects on linear growth after prolonged GH therapy. Data from a recent study of ours using GH in children with steroid-dependent inflammatory bowel disease showed that GH treatment was associated with increased lean body mass, decreased adiposity and increased linear growth. Marked increases in IGF-I concentrations and in kinetic measures of bone calcium accretion (using calcium tracers) were also observed, without any deterioration of disease activity scores or carbohydrate tolerance. In conclusion, GH therapy may play a role in the treatment of children on chronic steroids both as a growth promoting agent and as an anabolic agent on whole body protein and bone. Longer term studies will be needed to better define the safety and efficacy of this approach.
11771569 Overview on clinical data of dexibuprofen. 2001 Nov Several clinical trials, post-marketing surveillance studies and a meta-analysis were performed to obtain information about dose finding, pharmacokinetics, special indications, tolerability and compliance. In eight clinical trials, according to GCP, 1463 patients were included. Six of the trials were double-blind studies against placebo, racemic ibuprofen and diclofenac; the pharmacokinetic study and a long-term safety study were open studies. A meta-analysis of five clinical trials compared tolerability and safety data between dexibuprofen and racemic ibuprofen. Three PMS studies collected data on 7133 outpatients. All clinical trials and PMS studies have been published. In the dosage ratio 0.5:1, dexibuprofen was found to be at least as efficacious as racemic ibuprofen; 75% of the maximum daily dose of dexibuprofen was equally efficacious as 100% of MDD of diclofenac; no influence was found of meals on bioavailability and a significant doseresponse relationship; there was clinical efficacy in rheumatoid arthritis, ankylosing spondylitis, osteoarthritis of the hip, osteoarthritis of the knee, lumbar vertebral syndrome, distortion of the ankle joint and dysmenorrhoea; there was good tolerability compared to other NSAIDs: racemic ibuprofen showed a 30% and diclofenac a 90% higher incidence of adverse drug reactions; the long-term study stated a 15.2% adverse drug event incidence; the incidence of adverse drug reactions in the PMS studies was between 5.5% and 7.4%, and withdrawals were between 2.3% and 2.7%. In conclusion, dexibuprofen (Seractil) has the stature of a modern NSAID, combining the high efficacy of diclofenac with the good tolerability of ibuprofen, and need not hide behind the new generation of COX-2 inhibitors.
11698039 Kinin receptors in pain and inflammation. 2001 Oct 19 Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B(1) and B(2). Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg(9)-kinins). The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1 beta and tumor necrosis factor-alpha. This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response. The B(1) receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B(1) receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B(1) receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B(1) receptor deserves to be investigated further.
11588111 Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, dev 2001 Oct 1. Interleukin-12 (IL-12) may play a central role in the development and progression of rheumatoid arthritis by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated the effect of auranofin (AF), an anti-rheumatic gold compound, on IL-12 production in mouse macrophages and dendritic cells, and studied whether AF-mediated inhibition of IL-12 production could regulate a cytokine profile of antigen (Ag)-primed CD4(+) Th cells. 2. Treatment with AF significantly inhibited IL-12 production in lipopolysaccharide (LPS)-stimulated macrophages and also in CD40L-stimulated dendritic cells. AF-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. AF did not influence the cell surface expression of the class II MHC molecule and the costimulatory molecules CD80 and CD86. 3. Addition of recombinant IL-12 to cultures of AF-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in Ag-primed CD4(+) T cells. 4. The in vivo administration of AF resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with LPS or heat-killed Listeria monocytogenes (HKL), leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in Ag-primed CD4(+) T cells. 5. These findings may explain some known effects of AF including anti-rheumatic effects and the inhibition of encephalitogenicity, and point to a possible therapeutic use of AF in the Th1-mediated immune diseases such as autoimmune diseases.
11528521 Lack of association of a functionally relevant single nucleotide polymorphism of matrix me 2001 Aug Matrix metalloproteinase 1 (MMP-1) is necessary for degradation of interstitial collagen types I, II, and III, which are the major constituents of the extracellular matrix (ECM). Increased expression of MMP-1 has been correlated with invasiveness of certain malignancies and cartilage degradation in rheumatoid arthritis. Increased transcriptional activity of MMP-1 has been reported with a single nucleotide polymorphism (SNP) of the MMP-1 promoter. Systemic sclerosis (SSc) is characterized by increased accumulation and turnover of collagen and other components of ECM. Previous studies have reported increased expression of MMP-1 transcripts in SSc fibroblasts. Therefore, we sought to determine if SSc patients with early disease (< or =5 years) from a multi-ethnic cohort were more or less likely than ethnically-matched normal controls to have an increased frequency of the high promoter activity MMP-1 genotype and whether MMP-1 promoter genotypes correlated with any of the major clinical manifestations of SSc. The results show that the frequency of the high activity promoter genotype in either the heterozygous or homozygous state did not differ significantly between SSc patients and ethnically-matched controls, or between SSc patients with either diffuse or limited scleroderma. Furthermore, MMP-1 promoter genotypes did not significantly correlate with any of the major clinical manifestations of SSc.
11358009 Autoimmune disease-associated lymphadenopathy with histological appearance of T-zone dyspl 2001 Autoimmune disease-associated lymphadenopathy shows marked histopathological and clinical diversity. We describe the clinicopathological and immunohistochemical findings of nine cases of autoimmune disease-associated lymphadenopathy, which posed a serious differential diagnostic problem regarding T-zone dysplasia with hyperplastic follicles. There were two males and seven females aged 25 to 65 years (median 37 years). The patients had multicentric lymphadenopathy in association with clinical and laboratory findings suggestive of an "autoimmune disease". Four patients were diagnosed to have systemic lupus erythematosus (SLE), and the remaining five patients had antiphospholipid antibody syndrome and Sjogren's syndrome (SS), rheumatoid arthritis (RA), chronic thyroiditis, RA and SS, and SLE and SS, respectively. None of the nine patients developed malignant lymphomas during the follow-up periods from 44 to 225 months (median 103 months). The lesions were characterized by paracortical hyperplasia with prominent vascular proliferation and many lymphoid follicles with germinal centers. The paracortical area usually contained numerous small T-lymphocytes without cytological atypia, accompanied by a variable number of plasma cells, B-immunoblasts, and histiocytes. Polymerase chain reaction analysis demonstrated no clonal rearrangement of the T-cell receptor chain gene in four cases examined, although immunoglobulin heavy chain rearrangement was detected in only one case. These findings suggest that autoimmune disease-associated lymphadenopathy, especially SLE, shares the histological features with T-zone dysplasia with hyperplastic follicles. The nine cases presented here should be differentiated from T-zone lymphoma with follicles and angioimmunoblastic lymphoma with hyperplastic germinal centers. To avoid overdiagnosis and overtreatment, we emphasize the need to turn attention to these clinical and laboratory findings as well as to the morphological features.
11325013 Molecular mechanisms for alpha2-adrenoceptor-mediated regulation of synoviocyte population 2001 Mar The sympathetic nervous system has been indicated to influence the severity of inflammatory disease including rheumatoid arthritis. In this study, we elucidated the effects of catecholamine on the synovial cell populations. Stimulation with epinephrine or norepinephrine for 1-2 weeks dose- and time-dependently increased the number of synovial A (macrophage-like) cells but decreased that of B (fibroblast-like) cells. These responses in A and B cells were inhibited by the alpha2-antagonist yohimbine, the G-protein inactivator pertussis toxin and the phospholipase C (PLC) inhibitor U-73122. Furthermore, the protein kinase C (PKC) inhibitor calphostin C and mitogen-activated protein (MAP) kinase inhibitors PD98059 and wortmannin also abolished the norepinephrine effects on A and B cell numbers. In A cells cloned from an A and B cell mixture, norepinephrine also increased the cell number. In immunoblotting and immunocytostaining analyses, among the PKC isozymes, only PKC betaII immunoreactivity was observed in the cytoplasm of unstimulated A and B cells. After alpha2-adrenoceptor stimulation, PKC betaII immunoreactivity increased in the plasma membranes of both A and B cells with decreases in the cytoplasm. These findings indicated that alpha2-adrenoceptor stimulation of type A and B synoviocytes produced an increase and a decrease in the respective cell number, probably through Gi-coupled PLC activation and the resulting stimulation of the PKC betaII/MAP kinase.
11298088 A luminescent bioassay for thyroid blocking antibodies. 2001 Mar OBJECTIVE: Thyroid blocking antibodies (TBAb) have a role in the development of hypothyroidism and in the neonate are responsible for transient hypothyroidism. Specific measurement of TBAb requires a bioassay, but current methods are lengthy and cumbersome. We describe a rapid luciferase-based method for the detection of TBAb using the lulu* cell line which is suitable for the provision of a clinical service PATIENTS AND MEASUREMENTS: Chinese hamster ovary (CHO) cells were transfected with human TSH-R together with G418 resistance and a cAMP responsive luciferase construct. Stable pools of transfected cells were selected and clones identified by limiting dilution. Clone lulu* gave the best response to stimulation by TSH and was used to develop a bioassay for TBAb. The luminescent bioassay conditions have been optimized and validated using 12 serum samples from patients found to be TBAb positive in a bioassay using an established method quantifying cAMP by radioimmunoassay (RIA). The effect of thyroid stimulating antibodies (TSAb) on the calculation of Inhibition Index (InI) using two previously described formulae have been investigated and we have used serum containing both TSAb and TBAb to investigate detection of TBAb in samples containing more than one type of activity. RESULTS: Lulu* displays a dose dependent increase in luciferase expression in response to stimulation with bovine (b) TSH which is more effective in serum free medium than in salt free buffer. TSH stimulated luciferase expression can be inhibited by TBAb in either serum or an immunoglobulin preparation. Using optimized assay conditions, challenging 10% serum against 1 U/l bTSH in culture medium, we have tested 31 euthyroid sera to determine a reference range: InI values >23% were considered positive. Twelve samples previously shown to contain TBAb by an established method quantifying cAMP by RIA were positive by the luciferase-based assay. Of control sera, 20/20 systemic lupus erythematosus, 13/14 rheumatoid arthritis, 12/12 multinodular goitre were negative. We demonstrated that if more complex formulae are used to calculate InI, false positive TBAb results can be obtained in samples containing only TSAb. Finally, when sera contain both TSAb and TBAb, the net activity of stimulating and blocking antibodies is detected in the bioassay. Where TSAb are also present, analysis of serum may be required at several dilutions to detect TBAb. CONCLUSIONS: We describe the production of a new cell line, lulu*, and its use to develop a luminescent bioassay for TBAb suitable for clinical use. Comparing two established methods of calculating TBAb, we found that they do not give identical results. In light of this, the high prevalence reported for TBAb in some studies has to be considered with caution.
11092254 The liver in collagen diseases: pathologic study of 160 cases with particular reference to 2000 Oct AIMS/BACKGROUND: Among patients with collagen diseases, liver enzyme abnormalities are a relatively common phenomenon. To establish the liver pathology in collagen diseases, detailed pathologic studies were performed on the hepatic diseases in many patients, including various kinds of collagen diseases. METHODS: The livers from 160 patients (120 autopsy and 40 liver biopsy patients) were examined pathologically: 73 with systemic lupus erythematosus (SLE), 32 with rheumatoid arthritis (RA), 18 with polymyositis and dermatomyositis (PM and DM), 15 with systemic sclerosis (SSc), 11 with mixed connective tissue disease (MCTD) and 11 with polyarteritis nodosa (PAN). RESULTS: Liver diseases were divided into three groups: hepatic arteritis, liver diseases associated with collagen diseases (primary biliary cirrhosis, PBC; autoimmune hepatitis, AIH; nodular regenerative hyperplasia of the liver, NRH) and other liver diseases. Hepatic arteritis presenting the features of the PAN type of necrotizing arteritis was found in 27 autopsy patients. The incidence of arteritis in autopsy patients was 100% in PAN and 8.3-25% in other collagen diseases. Primary biliary cirrhosis was observed in 9 patients, 7 of whom (3 with SSc, 2 with RA, 1 with PM and DM, and 1 with MCTD) had antimitochondrial antibodies (AMA)-positive PBC, and 2 SLE patients had AMA-negative PBC. Three patients (2 with SLE and 1 with MCTD) were diagnosed clinicopathologically as having AIH. However, 3 patients (1 with SLE, 1 with MCTD and 1 with PM and DM) with clinical, biochemical and serologic data indicating probable AIH were excluded from the group with AIH association because of the liver histology (no characteristic features of AIH) and clinical course. These results indicated that data without histologic assessments of the liver are not adequate for diagnosing AIH in collagen diseases. Nodular regenerative hyperplasia of the liver was observed in 7 patients (5 with SLE, 1 with SSc and 1 with PAN). CONCLUSION: The present study offers data that are useful for the diagnosis and treatment of patients with collagen diseases and liver abnormalities.
11036931 Vascular endothelial growth factor and the regulation of angiogenesis. 2000 The development of a vascular supply is essential not only for organ development and differentiation during embryogenesis but also for wound healing and reproductive functions in the adult Folkman, 1995). Angiogenesis is also implicated in the pathogenesis of a variety of disorders: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis (Folkman, 1995; Garner, 1994). Several potential regulators of angiogenesis have been identified, including fibroblast growth factor-a (aFGF), bFGF, transforming growth factor-alpha (TGF-alpha), TGF-beta, hepatocyte growth factor/scatter factor (HGF/SF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and interleukin-8 (IL-8) (Folkman and Shing, 1992; Risau, 1997). More recently, the angiopoietins, the ligands of the Tie-2 receptor (Suri et al., 1996; Maisonpierre et al., 1997), have been identified. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific mitogen. The finding that VEGF was potent and specific for vascular endothelial cells and, unlike bFGF, freely diffusible, led to the hypothesis that this molecule plays a unique role in the regulation of physiological and pathological angiogenesis (Ferrara and Henzel, 1989: Leung et al., 1989). Over the last few years, several additional members of the VEGF gene family have been identified, including placenta growth factor (PIGF) (Maglione et al., 1991,1993), VEGF-B (Olofsson et al., 1996), VEGF-C (Joukov et al., 1996; Lee et al., 1996), and VEGF-D (Orlandini et al., 1996. Achen et al., 1998). There is compelling evidence that VEGF plays an essential role in the development and differentiation of the cardiovascular system (Ferrara and Davis-Smyth, 1997).
11034708 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. Updated Search conducted August 2000. No new trials were found. 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.
10919278 Dexamethasone suppresses tumor necrosis factor-alpha-induced apoptosis in osteoblasts: pos 2000 Aug Ceramide has been proposed as a second messenger molecule implicated in a variety of biological processes, including apoptosis. Recently, it has been reported that tumor necrosis factor-alpha (TNF-alpha) activates the release of ceramide and that ceramide acts as a mediator for the TNF-alpha-induced stimulation of the binding affinity of nuclear factor-KB (NF-KB), a ubiquitous transcription factor of particular importance in immune and inflammatory responses. In this study we demonstrate that dexamethasone, which reduces the production of ceramide, significantly inhibits TNF-alpha-induced activation of NF-KB, c-Jun N-terminal kinase, also known as stress-activating protein kinase, caspase-3-like cysteine protease, redistribution of cytochrome c, and apoptosis in MC3T3E1 osteoblasts. Compared with TNF-alpha-induced JNK activation, ceramide elicits a more rapid activation of JNK within 30 min. C2-ceramide activates NF-KB and caspase-3 like protease to the same degree and with kinetics similar to those of TNF-alpha. This study provides evidence that the release of ceramide may be required as a second messenger in TNF-alpha-induced apoptosis. These results also suggest a regulatory role for dexamethasone in TNF-alpha-induced apoptosis via inhibition of ceramide release. Therefore, our in vitro results suggest that therapies targeted at the inhibition of ceramide release may abrogate inflammatory processes in TNF-alpha-related diseases, including rheumatoid arthritis and periodontitis.
10726797 Uveitis in children: population-based study in Finland. 2000 Feb PURPOSE: To investigate the incidence and prevalence rates of different types of uveitis in children, and to compare them with the rates in adults. SUBJECTS AND METHODS: For this population-based retrospective study the medical records of all residents of the district of Turku University Hospital with a diagnosis of uveitis seen at the Eye Clinic of Turku University Hospital during the years 1980-1982 and 1988 were reviewed. RESULTS: A total of 1122 uveitis cases were identified, and 55 (4.9%) of them were children under 16 years. The incidence per 100 000 population per year for all uveitis cases in children was 4.3 (95% confidence interval [CI], 2.2 to 6.4), and the prevalence was 27.9 (95% CI, 17.1 to 38.6), which was significantly lower compared with the rates in adults (p=0.001 for incidence and prevalence). The vast majority of children, 50 (90.9%), had anterior uveitis (AU), and the incidence and prevalence rates of AU were significantly lower than in adults (p=0.001 for incidence and prevalence). Three (5.5%) children had posterior uveitis (PU), but there was no significant difference in the incidence and only marginally significant difference in the prevalence rate of PU in children compared with the rates in adults (p=0.33 for incidence, and p=0.07 for prevalence). Only one case (1.8%) was found with intermediate and one with panuveitis, but no new cases. The commonest diagnostic groups in children were AU associated with juvenile rheumatoid arthritis, idiopathic acute anterior uveitis, and idiopathic chronic anterior uveitis. Toxoplasmic retinochoroiditis was found in all of the PU cases with the incidence 0.3, and the prevalence 1.1, which did not differ significantly from the rates in adults (p=1.0 for incidence, and p= 0.48 for prevalence). CONCLUSION: Uveitis is rarer in children than in adults. However, in contrast to studies from tertiary referral centers, the distribution of different forms of uveitis in children in this population-based study seems to resemble the distribution in adults.
10657660 Selective inhibition of monocyte chemoattractant protein-1 gene expression in human embryo 2000 Feb 15 Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is expressed by a variety of tissue cells in response to inflammatory stimuli, such as IL-1beta, TNF-alpha, and IFN-gamma. A major function of MCP-1 is the recruitment and activation of monocytes and T lymphocytes. Overexpression of MCP-1 has been implicated in a number of diseases, including glomerulonephritis and rheumatoid arthritis, indicating that the modulation of MCP-1 activity and/or expression is a desired therapeutic strategy. In the present study, our aim was to test whether the MCP-1 expression could be inhibited at the transcriptional level using triple helix-forming oligonucleotides (TFOs). We designed a TFO targeted to the SP-1 binding site in the human MCP-1 gene promoter. Gel mobility shift assays demonstrated that the phosphodiester TFO formed a sequence-specific triplex with its dsDNA target with an EC50 of approximately 1.9 x 10(-7) M. The corresponding phosphorothioated oligonucleotide was also effective in this assay with an 8-fold higher EC50 value. Binding of the TFO to the target DNA prevented the binding of rSP-1 and of nuclear proteins in vitro. The TFO could also partially inhibit endogenous MCP-1 gene expression in cultured human embryonic kidney cells. Treatment of TNF-alpha-stimulated human embryonic kidney 293 cells with the TFO inhibited the secretion of MCP-1 in a dose-dependent manner (up to 45% at 5 microM oligonucleotide). The inhibition of MCP secretion was caused at the level of gene transcription, because MCP-1 mRNA levels in oligonucleotide-treated cells were also decreased by approximately 40%.
10655505 Accelerated development of IgG autoantibodies and autoimmune disease in the absence of sec 2000 Feb 1 Individuals with systemic lupus erythematosus and rheumatoid arthritis are characterized by the presence of high levels of circulating IgM and IgG autoantibodies. Although IgG autoantibodies often are pathogenic, the role of IgM autoantibodies in autoimmune disease is not clear. Using mice that are unable to secrete IgM but are able to express surface IgM and IgD and to secrete other classes of immunoglobulins, we examined the effect of the absence of secreted IgM in the development of IgG autoantibodies and autoimmune disease in lupus-prone lymphoproliferative (lpr) mice. Compared with regular lpr mice, lpr mice that lack secreted IgM developed elevated levels of IgG autoantibodies to double-stranded DNA and histones and had more abundant deposits of immune complexes in the glomeruli; they also suffered more severe glomerulonephritis and succumbed to the disease at an earlier age. Similarly, the absence of secreted IgM also resulted in an accelerated development of IgG autoantibodies in normal mice. These findings suggest that secreted IgM, including IgM autoantibodies produced naturally or as part of an autoimmune response, may lessen the severity of autoimmune pathology associated with IgG autoantibodies.
10428225 Eliminating patellofemoral complications in total knee arthroplasty: clinical and radiogra 1999 Jun This study reports the minimum 5-year follow-up of our experience with the Duracon Total Knee Arthroplasty System. A total of 121 consecutive total knee replacements using the Duracon system (Howmedica, Rutherford, NJ) were performed in 104 patients. Three patients died before the 5-year follow-up and were excluded from the final evaluation. The remaining 118 knees (101 patients) were assessed at a mean follow-up of 65 months (range, 60-80 months). The knee diagnoses were osteoarthritis in 97 patients, rheumatoid arthritis in 2 patients, osteonecrosis in 1 patient, and pigmented villonodular synovitis in 1 patient. The mean age was 70 years (range, 28-85 years). There were no reoperations for aseptic loosening, and there have been no reoperations for patellofemoral problems. At final follow-up evaluation, 112 knees (96%) had good or excellent results, and 6 knees (4%) had poor clinical results or went on to revision. For the surviving knees, the preoperative Knee Society objective score improved from a mean of 52 points (range, 20-72 points) to a final follow-up mean of 94 points (range, 66-100 points). Five knees needed reoperations: 2 knees in 1 patient because of acute hematogenous infection at 12 months, 1 knee because of a supracondylar femur fracture, 1 because of a patellar tendon rupture, and 1 to increase polyethylene thickness because of instability. The lack of aseptic loosening at the minimum 5-year follow-up compares favorably with any cemented or cementless series of knee replacement. The almost complete absence of patellofemoral complications in this series also indicates that the design changes, with particular attention to the trochlea design and patellofemoral contact throughout full flexion, have achieved their intended purpose. The results are encouraging at midterm, awaiting true long-term (15-20 years) follow-up.
10352247 Selection and long-term persistence of reactive CTL clones during an EBV chronic response 1999 Jun 1 Recent studies have suggested that the diversity of TCR repertoire after primary immunization is conserved in memory T cells and that a progressive narrowing of this repertoire may take place during recall infections. It now remains to be investigated which parameters determine the repertoire of the memory response and possibly restrict its diversity after subsequent antigenic challenges. To address this question, we took advantage of a panel of CD8+ T cell clones from the joint of a rheumatoid arthritis patient and selected for their reactivity against a single MHC/peptide complex. Characterization of both TCR chains documented a great diversity among those clones and the persistence of clonotypes over a 2-yr period. Strikingly, despite the observed repertoire heterogeneity, all clones displayed a narrow range of MHC/peptide density requirements in cytotoxicity assays (ED50 between 9 and 36 nM). TCR affinities were then indirectly estimated by blocking CD8 interaction with an anti-CD8 mAb. We found a wide range of TCR affinities among the different clonotypes that segregated with Vbeta usage. We thus propose that during an in vivo chronic response, a narrow range of avidity of the TCR-CD8 complex conditions long-term clonotype persistence, and that the level of CD8 contribution is adjusted to keep clonotypes with variable TCR affinities within this avidity window.
10201965 Autoantibodies to T cell costimulatory molecules in systemic autoimmune diseases. 1999 Apr 1 To determine whether antilymphocyte Abs to T cell costimulatory molecules are generated in patients with autoimmune diseases and, if they exist, to clarify the mechanism of their production and pathological roles, we investigated the presence of autoantibodies to CTLA-4 (CD152), CD28, B7-1 (CD80), and B7-2 (CD86) in serum samples obtained from patients with various autoimmune diseases and from normal subjects using recombinant fusion proteins. In ELISAs, anti-CD28, anti-B7-1, and anti-B7-2 Abs were rarely seen, whereas anti-CTLA-4 Abs were detected in 8.2% of the patients with systemic lupus erythematosus, 18.8% of those with rheumatoid arthritis, 3.1% of those with systemic sclerosis, 31.8% of those with Behçet's disease, 13.3% of those with Sjögren's syndrome, and 0% of healthy donors. This reactivity was confirmed by immunoblotting. More importantly, the purified anti-CTLA-4 Abs reacted with CTLA-4 expressed on P815 cells by flow cytometry. In addition, we found at least three epitopes on the CTLA-4 molecule. Furthermore, among the patients with Behçet's disease, uveitis was seen significantly less frequently in the anti-CTLA-4 Ab-positive patients. Taken collectively, these data indicate that anti-CTLA-4 autoantibodies are generated in systemic autoimmune diseases by an Ag-driven mechanism and may modulate the immune response in vivo by binding to CTLA-4 on T cells.