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ID PMID Title PublicationDate abstract
10334680 Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patie 1999 Jan OBJECTIVE: To examine the expression of the matrix metalloproteinase, MMP-1, and the cysteine proteases, cathepsin B (CB) and cathepsin L (CL), in the synovial membrane (SM) of patients with early inflammatory arthritis. METHODS: Samples of SM were obtained by blind needle biopsy or needle arthroscopy from inflamed knees of 28 patients with early inflammatory arthritis (mean disease duration 10.2 months, range 2 weeks-18 months). Sixteen patients had rheumatoid arthritis (RA), nine psoriatic arthritis and there was one each with ankylosing spondylitis, gout and an undifferentiated arthritis. Comparison was made with tissue from two patients with established erosive RA and three normal synovial tissue samples. In situ hybridization was performed using digoxigenin-labelled RNA probes. RESULTS: MMP-1, CB and CL were expressed in all patients with early arthritis and in established erosive RA, whereas normal synovium showed only scanty expression. The three proteases were prominent in perivascular infiltrates and endothelial cells of early arthritis tissue. MMP-1 was observed primarily in the lining layer, but was also evident in the sublining area. CB and CL were expressed to a lesser extent in the lining layer, and were present mainly in the subintima. The three proteases were not found in lymphoid aggregrates. No differences were observed between the disease categories. CONCLUSIONS: The detection of MMP-1, CB and CL in the synovium shortly after symptom onset implies that the potential for joint destruction exists at a very early stage in the disease. In addition, the perivascular and endothelial cell expression suggests a role for these proteases in mononuclear cell influx to the inflamed synovium and in angiogenesis.
11315937 Hereditary angioedema with a de novo mutation of exon 8 in the C1 inhibitor gene showing r 2001 Apr We describe a patient with hereditary angioedema (HAE), showing recurrent edema around the peripheral joints. Her symptoms began at the age of 18 with hand swelling distal to the wrist joints. Until she was referred to our hospital 3 years after her initial symptoms, she was still undiagnosed, although she was suspected of having rheumatoid arthritis. Laboratory examination showed reduced levels of CH50 and C4 with normal C3 levels. The C1 inhibitor (C1-INH) was decreased to 5 mg/ml, with remarkably reduced activity. Although these findings were compatible with a diagnosis of HAE, there were no episodes of skin edema in her family. To establish the diagnosis, we carried out DNA analysis of the C1-INH gene, which revealed a newly identified de novo mutation of G to A at nucleotide 16869 in exon 8. As described in this patient, localized edema around the peripheral joints may be the only manifestation of HAE. HAE should therefore be taken into consideration for the differential diagnosis of joint swelling.
11759232 [New therapy developments in rheumatoid arthritis]. 2001 Oct Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
11102771 Present difficulties and future promise of MHC multimers in autoimmune exploration. 2000 Dec Class I tetramers have been used to track cytotoxic T cells during bacterial and viral infections. During the past year, the use of such molecules has revealed important information about the role of CD8(+) T cells in autoimmune diabetes. Furthermore, class II multimers have been produced and successfully used to stain autoreactive CD4(+) T cells from patients with rheumatoid arthritis or Borrelia-burgdorferi-induced Lyme arthritis.
9022804 Analogues of methotrexate in rheumatoid arthritis. 1. Effects of 10-deazaaminopterin analo 1997 Jan 31 Carbonation of the dianions (LDA) of 5-methylthiophene-2-carboxylic, 2-methylpyridine-5-carboxylic, and 3-methylpyridine-6-carboxylic acids provided the respective carboxy heteroarylacetic acids. The crude diacids were directly esterified in MeOH-HCl to afford the diesters. Alkylation of the sodio anions with ethyl iodide yielded the appropriate alpha-ethyl diesters. The anions of the various diester substrates were then alkylated by 2,4-diamino-6-(bromomethyl)-pteridine followed by ester saponification at room temperature to afford the respective 2,4-diamino-4-deoxy-10-carboxy-10-deazapteroic acids. The 10-carboxyl group was readily decarboxylated by heating in DMSO at temperatures of 110-135 degrees C to give the diamino 10-deaza heteropteroic acid intermediates. Coupling with diethyl L-glutamate followed by ester hydrolysis afforded the target aminopterins. The analogues were evaluated for antiinflammatory effect in the mouse type II collagen model. The thiophene analogue of 10-ethyl-10-deazaaminopterin was found to be an effective inhibitor in terms of reduced visual evidence of inflammation and swelling as determined by caliper measurement.
9461136 Efficacy of arthroscopic lysis and lavage in patients with temporomandibular joint symptom 1998 Feb PURPOSE: This study evaluated the efficacy of arthroscopic lysis and lavage in patients with temporomandibular joint (TMJ) symptoms and generalized osteoarthritis (GOA) or rheumatoid arthritis (RA). PATIENTS AND METHODS: Twenty-three GOA patients and 23 RA patients were evaluated after 1 year. RESULTS: Seventeen of 23 patients (74%) in the RA group improved after arthroscopic lysis and lavages compared with 10 of 23 (43%) of the GOA patients. Lateral joint tenderness, crepitation, maximal opening, and maximal protrusion showed most improvement in the RA group. CONCLUSIONS: On the basis of this short-term follow-up study, arthroscopic lysis and lavage seem to provide an effective treatment for TMJ pain and dysfunction in RA patients but not in GOA patients.
9779300 Anti-neutrophil cytoplasmic antibodies in 566 European patients with systemic lupus erythe 1998 Sep OBJECTIVES: To evaluate, in a cohort of 566 patients with systemic lupus erythematosus (SLE) drawn from 11 European centres: (i) the prevalence of ANCAs and their subspecificities in a large series of European SLE patients; (ii) the possible associations of ANCA with the most common clinical manifestations of the disease; and (iii) whether ANCAs correlate with some of the autoantibodies commonly found in SLE. METHODS: ANCA detection was performed by indirect immunofluorescence (IIF), and by ELISA for lactoferrin (LF), myeloperoxydase (MPO), proteinase3 (PR3) and lysozyme (LZ) subspecificities. RESULTS: The prevalence of ANCA was 16.4% (IIF). The prevalence of LF was 14.3%, LZ 4.6%, MPO 9.3%, and PR3 1.7%. Our results show that ANCA is associated with certain clinical manifestations of SLE. In particular, positive correlations were found between IIF ANCA and serositis (p = 0.026), livedo reticularis (p = 0.01), venous thrombosis (p = 0.03) and arthritis (p = 0.04), while anti-LF antibodies were associated with serositis (p = 0.05) and livedo reticularis (p < 10(-3). Nevertheless, multivariate analysis demonstrated that other autoantibodies, such as aCL and SSA/Ro, are more closely correlated than ANCA with some of the aforementioned clinical features. CONCLUSION: Our results demonstrate that ANCA are detectable in SLE sera and that some of them are associated with particular clinical manifestations. Whether ANCA plays a direct pathogenetic role in the vascular damage of SLE or only represents an epiphenomenon or a marker of disease activity remains to be elucidated.
11557363 Collagen type II C-telopeptide fragments as an index of cartilage degradation. 2001 Sep We report the development of an assay for measurement of the urinary concentration of collagen type II C-telopeptide fragments. This assay was developed for providing a specific marker of joint metabolism. A monoclonal antibody, recognizing a linear six amino acid epitope from the middle region of the collagen type II C-telopeptide was used in a competitive enzyme-linked immunoassay (ELISA) format for measurement of urine samples. The technical performance and specificity of the assay was evaluated and a panel of samples from patients with rheumatoid arthritis (RA) (n = 27), osteoarthritis (OA) (n = 29), Paget's disease (n = 9), and healthy controls (n = 428) was measured in the assay. The ELISA was specific for the peptide EKGPDP derived from collagen type II C-telopeptide: it did not recognize peptides from the N-telopeptide of the molecule or from other collagen types. Collagen type II C-telopeptide fragments measured in the assay resisted seven freeze-thaw cycles and >20 h of storage at room temperature. RA and OA patients showed significant 2.33-fold (95% confidence interval [CI] 1.50-3.16) and 1.53-fold (CI 1.24-1.82) elevations in CartiLaps concentration, respectively. Paget's disease patients did not have elevated CartiLaps levels. RA patients with radiological evidence of cartilage damage had significantly higher (1.79-fold, CI 1.04-2.54) CartiLaps levels than RA patients without radiological evidence of cartilage destruction. The Cartilaps assay showed high technical precision and an ability to differentiate populations with an elevated joint metabolism from normal controls. This suggests that the assay may have clinical value in assisting in the diagnosis of joint diseases and in monitoring progression and therapy in RA and OA.
11086103 Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in 2000 Dec 1 Rheumatoid arthritis (RA) is characterized by the accumulation of CD4(+) memory T cells in the inflamed synovium. To address the mechanism, we analyzed chemokine receptor expression and found that the frequency of CXC chemokine receptor (CXCR)4 expressing synovial tissue CD4(+) memory T cells was significantly elevated. CXCR4 expression could be enhanced by IL-15, whereas stromal cell-derived factor (SDF)-1, the ligand of CXCR4, was expressed in the RA synovium and could be increased by CD40 stimulation. SDF-1 stimulated migration of rheumatoid synovial T cells and also inhibited activation-induced apoptosis of T cells. These results indicate that SDF-1-CXCR4 interactions play important roles in CD4(+) memory T cell accumulation in the RA synovium, and emphasize the role of stromal cells in regulating rheumatoid inflammation.
9653166 Efficient adenoviral infection with IkappaB alpha reveals that macrophage tumor necrosis f 1998 Jul 7 Tumor necrosis factor (TNF) alpha has been shown to be a major therapeutic target in rheumatoid arthritis with the success of anti-TNFalpha antibody clinical trials. Although signaling pathways leading to TNFalpha expression have been studied in some detail, there is evidence for considerable differences between individual cell types. This prompted us to investigate the intracellular signaling pathways that result in increased TNFalpha synthesis from macrophages in the diseased synovial joint tissue. Using an adenoviral system in vitro we report the successful delivery of genes to more than 95% of normal human macrophages. This permitted us to show, by using adenoviral transfer of IkappaB alpha, the natural inhibitor of NF-kappaB, that induction of TNFalpha in normal human macrophages by lipopolysaccharide, but not by some other stimuli, was inhibited by 80%. Furthermore the spontaneous production of TNFalpha from human rheumatoid joint cell cultures was inhibited by 75%, indicating that the NF-kappaB pathway is an essential step for TNFalpha synthesis in synovial macrophages and demonstrating that NF-kappaB should be an effective therapeutic target in this disease.
11695246 What have we learned from the large outcomes trials of COX-2 selective inhibitors? The rhe 2001 Nov The cyclooxygenase (COX)-2 selective inhibitors celecoxib and rofecoxib have been found to be more effective than placebo and comparably effective to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of patients with osteoarthritis and rheumatoid arthritis. Two large outcome studies, the Celecoxib Long-term Arthritis Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, were conducted to test the hypothesis that patients receiving a COX-2 selective inhibitor would have significantly fewer clinically important upper gastrointestinal events than patients taking nonselective NSAIDs. This article critically reviews the design and results of these trials. Both trials found that arthritis patients not taking low-dose aspirin (325 mg/day or less) who were randomized to receive COX-2 selective inhibitors had significantly fewer symptomatic and complicated ulcers than patients randomized to nonselective NSAIDs. A significant risk reduction was not demonstrated, however, in patients in the CLASS trial who were taking low-dose aspirin, itself an independent risk factor for the endpoint. These data validate the COX-2 hypothesis and support recommendations that a COX-2 selective inhibitor should be used in the treatment of patients at increased risk for symptomatic and complicated ulcers. Further studies are needed to determine whether COX-2 selective inhibitors are safer than nonselective NSAIDs when used in patients receiving low-dose aspirin. The COX-2 selective inhibitors have a similar profile of renal adverse events to nonselective NSAIDs. The increased rate of cardiovascular thromboembolic adverse events among patients randomized to rofecoxib compared to those randomized to naproxen in the VIGOR trial is consistent with the lack of an anti-platelet effect for this COX-2 selective inhibitor. This emphasizes the need for the use of low-dose aspirin in patients at risk for such events, especially myocardial infarction.
11123060 Familial autoimmunity and the idiopathic inflammatory myopathies. 2000 Jun Many lines of evidence suggest that autoimmune diseases result from chronic immune activation following environmental exposures in genetically susceptible individuals. A genetic basis for autoimmunity is supported by twin and family studies, candidate gene investigations, animal models, and whole genome microsatellite scans. These findings predict, and clinical observations support, familial clustering of a number of individual autoimmune diseases, notably lupus, multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, and recently the idiopathic inflammatory myopathies. Yet, not only is the same autoimmune disease increased in prevalence in pedigrees of persons affected with a given disorder, but other autoimmune diseases are as well. We review these data and propose a hypothesis consistent with these findings. This model posits that a rheumatic disease, as currently classified, is actually composed of a number of elemental disorders. Each of these is defined by the minimal necessary and sufficient environmental exposures and genes that result in a pathology leading to a given sign-symptom complex.
10049750 Oxidation of alpha1-proteinase inhibitor by the myeloperoxidase-hydrogen peroxidase system 1999 Feb 24 We have demonstrated previously that patients with rheumatoid arthritis (RA) show an increase in serum and synovial fluid levels of complexes between alpha1-proteinase inhibitor (alpha1PI) and IgA. These are believed to form through disulfide binding between the Cys232 residue on alpha1PI and the penultimate cysteine residue (Cys471) of the IgA alpha chain. The mechanism for this has not been elucidated. We show here that alpha1PI oxidized by the myeloperoxidase-hydrogen peroxide (MPO-H2O2) system promotes the formation of IgA-alpha1PI complexes when incubated with IgA and that such complexes have no inhibitory activity against porcine pancreatic elastase (PPE). The activity of alpha1PI was considerably reduced also in IgA-alpha1PI complexes isolated from serum of an RA patient. We suggest that formation of IgA-alpha1PI complexes in inflammation may involve oxidation of alpha1PI, and as a consequence the alpha1PI in such complexes has reduced elastase inhibitory activity.
11121549 Rapid quantitation of proinflammatory and chemoattractant cytokine expression in small tis 2000 Dec 1 The analysis of cytokine profiles plays a central part in the characterization of disease-related inflammatory pathways and the identification of functional properties of immune cell subpopulations. Because tissue biopsy samples are too small to allow the detection of cytokine protein, the detection of mRNA by RT-PCR analysis is often used to investigate the cytokine milieu in inflammatory lesions. RT-PCR itself is a qualitative method, indicating the presence or absence of specific transcripts. With the use of internal or external standards it may also serve as a quantitative method. The most widely accepted method is quantitative competitive RT-PCR, based on internal shortened standards. Recently, online real-time PCR has been introduced (LightCycler), which allows quantitation in less than 30 min. Here, we have tested its use for the analysis of cytokine gene expression in different experimental in vitro and ex vivo settings. First, we compared quantitative competitive RT-PCR with real-time RT-PCR in the quantitation of transcription levels of the CD4(+) cell-specific chemoattractant Interleukin-16 during the maturation of monocyte-derived dendritic cells, and found a good correlation between both methods. Second, differences in the amounts of IL-16 mRNA in synovial tissue from patients with rheumatoid arthritis and osteoarthritis as assessed by real-time RT-PCR paralleled differences in the level of IL-16 protein in the synovial fluid. Finally, we employed real-time RT-PCR to study the cutaneous expression of several cytokines during experimental immunomodulatory therapy of psoriasis by Interleukin-10, and demonstrate that the technique is suitable for pharmacogenomic monitoring. In summary, real-time RT-PCR is a sensitive and rapid tool for quantifying mRNA expression even with small quantities of tissue. The results obtained do not differ from those generated by quantitative competitive RT-PCR.
11136885 The impact of rheumatoid arthritis on employment status in the early years of disease: a U 2000 Dec OBJECTIVE: To establish the prevalence of work disability and predictors of change in employment status in patients with early rheumatoid arthritis (RA). SETTING: The Norfolk Arthritis Register (NOAR), a primary-care based inception cohort of patients with recent-onset inflammatory arthritis. METHODS: Two cohorts of patients notified to NOAR, who satisfied the 1987 ACR criteria for RA at the time of notification (baseline) and who were economically active at the time of RA symptom onset, were identified. Cohort 1 consisted of 160 patients with an onset of RA between 1989 and 1992, and was followed for a mean of 8.6 yr from symptom onset. For 110 of these cases, a control group, matched for age, gender and employment status at baseline, was identified from the local population. Their employment histories were compared in 1995. Cohort 2 consisted of 134 patients with an onset of RA between 1994 and 1997, and was followed for a mean of 4.1 yr from symptom onset. RESULTS: One-third of RA cohort 1 had stopped working on the grounds of ill health by 1995. The baseline health assessment questionnaire (HAQ) score was the most important predictor of work disability. These patients were 32 times more likely to stop work on health grounds than the matched controls. The rates for work disability for the RA cases 1, 2, 5 and 10 yr after symptom onset were 14, 26, 33 and 39% respectively. For cohort 2, the rates for work disability 1 and 2 yr from onset were 23 and 33% respectively. CONCLUSION: Work disability is an important outcome in RA patients of working age. Many people stop working very early in the disease process, often before they are referred to hospital or started on disease-modifying anti-rheumatic drugs. Although the peak rates for work disability are in the early years, people with RA continue to leave the work force several years after onset. Thus, the recent move to earlier, more aggressive treatment has had no effect on the rates of work disability.
10765925 Production of tissue inhibitor of metalloproteinases 3 is selectively enhanced by calcium 2000 Apr OBJECTIVE: To determine the effects of calcium pentosan polysulfate (CaPPS) on the production of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP), in cultures of rheumatoid synovial fibroblasts. METHODS: The production of MMP-1, -2, -3, -7, -8, -9, and -13 and of TIMP-1, -2, -3, and -4 in cultured rheumatoid synovial fibroblasts treated with 0.1, 1, and 10 microg/ml CaPPS in the presence and absence of 100 units/ml interleukin-1alpha (IL-1alpha) was examined by a sandwich enzyme immunoassay system and/or immunoblotting. The messenger RNA (mRNA) expression of TIMP-3 and membrane type 1 MMP was determined by Northern blotting, and the cells expressing TIMP-3 gene in rheumatoid synovium were identified by in situ hybridization. The synthesis and secretion of TIMP-3 protein were monitored by pulse-chase experiments. TIMP-3 was immunolocalized in untreated or CaPPS-treated rheumatoid synovial fibroblasts and synovium using an avidin-biotin-peroxidase complex method. RESULTS: Treatment of cultured rheumatoid synovial fibroblasts with CaPPS resulted in a dose-dependent increase in the production of TIMP-3 in both cell lysates and media from the treated cells. However, CaPPS did not affect the levels of the other MMPs or TIMPs examined. The production of TIMP-3 was further enhanced in the cells treated with both IL-1alpha and CaPPS. Immunohistochemistry confirmed the enhanced production of TIMP-3 by cells exposed to CaPPS. The mRNA level of TIMP-3 increased 3.4-fold by treating rheumatoid synovial fibroblasts with IL-1alpha, but CaPPS itself did not alter the expression levels in the IL-1alpha-treated or -untreated cells. Pulse-chase studies demonstrated that translation for TIMP-3 protein was enhanced by CaPPS treatment. In situ hybridization and immunohistochemistry indicated that TIMP-3 was expressed mainly in the hyperplastic lining cells of rheumatoid synovium, and that the production of this protein by these immunoreactive lining cells was significantly increased by treatment with CaPPS. CONCLUSION: The present study is the first to demonstrate that the new antiarthritic drug, CaPPS, selectively enhanced TIMP-3 production at the posttranscription level in cultured rheumatoid synovial fibroblasts and in the lining cells of rheumatoid synovium. By this mechanism, CaPPS may be able to modulate joint tissue destruction in rheumatoid arthritis.
11339515 Comparison of intramuscular and oral meloxicam in rheumatoid arthritis patients. 2001 Mar OBJECTIVE: This double-blind, double-dummy, two-way comparative trial evaluated the overall efficacy and tolerability of intramuscular (im) vs oral meloxicam. SUBJECTS: 346 patients with rheumatoid arthritis (RA). TREATMENT AND METHODS: 173 patients in each group were randomised to receive either im meloxicam (15 mg) plus a placebo tablet, or oral meloxicam (15 mg) plus a placebo injection for 7 days. RESULTS: Significant (p < 0.001) improvements in overall pain and disease activity were observed by patients treated with im and oral meloxicam, with no significant difference between treatments. The im formulation was better than the oral tablet in terms of rapidity of action (p=0.012), global efficacy (p=0.030) and duration of morning stiffness (p=0.026). Local tolerability of im meloxicam was very good and comparable with placebo injections. CONCLUSION: Oral and im meloxicam (15 mg) were both effective and well-tolerated for acute exacerbations of RA. The im formulation had some advantages, such as a faster onset of action.
10410272 Rheumatoid arthritis associated with methotrexate-induced pneumonitis: improvement with i. 1999 May Pneumonitis is one of the most serious adverse effects associated with low-dose weekly methotrexate (MTX) therapy. Immediate cessation of MTX, and the introduction of oxygen therapy and glucocorticoids usually results in a dramatic improvement in the pulmonary toxicity. We report here a case of MTX-induced pneumonitis in a patient with rheumatoid arthritis (RA). Severe hypoxemia and interstitial infiltration in both lung fields did not respond to the withdrawal of MTX and the administration of oxygen and steroid pulse therapy. When intravenous cyclophosphamide (CYC) pulse therapy was initiated, however, rapid physiologic and radiographic improvement was seen. Our case suggests that CYC treatment may have a beneficial effect on MTX-induced pneumonitis that is resistant to steroid therapy.
10659758 Development and construction of a neutron beam line for accelerator-based boron neutron ca 2000 Jan A potential application of the 10B(n, alpha)7Li nuclear reaction for the treatment of rheumatoid arthritis, termed Boron Neutron Capture Synovectomy (BNCS), is under investigation. In an arthritic joint, the synovial lining becomes inflamed and is a source of great pain and discomfort for the afflicted patient. The goal of BNCS is to ablate the synovium, thereby eliminating the symptoms of the arthritis. A BNCS treatment would consist of an intra-articular injection of boron followed by neutron irradiation of the joint. Monte Carlo radiation transport calculations have been used to develop an accelerator-based epithermal neutron beam line for BNCS treatments. The model includes a moderator/reflector assembly, neutron producing target, target cooling system, and arthritic joint phantom. Single and parallel opposed beam irradiations have been modeled for the human knee, human finger, and rabbit knee joints. Additional reflectors, placed to the side and back of the joint, have been added to the model and have been shown to improve treatment times and skin doses by about a factor of 2. Several neutron-producing charged particle reactions have been examined for BNCS, including the 9Be(p,n) reaction at proton energies of 4 and 3.7 MeV, the 9Be(d,n) reaction at deuteron energies of 1.5 and 2.6 MeV, and the 7Li(p,n) reaction at a proton energy of 2.5 MeV. For an accelerator beam current of 1 mA and synovial boron uptake of 1000 ppm, the time to deliver a therapy dose of 10,000 RBEcGy ranges from 3 to 48 min, depending on the treated joint and the neutron producing charged particle reaction. The whole-body effective dose that a human would incur during a knee treatment has been estimated to be 3.6 rem or 0.75 rem, for 1000 ppm or 19,000 ppm synovial boron uptake, respectively, although the shielding configuration has not yet been optimized. The Monte Carlo design process culminated in the construction, installation, and testing of a dedicated BNCS beam line on the high-current tandem electrostatic accelerator at the Laboratory for Accelerator Beam Applications at the Massachusetts Institute of Technology.
11263771 Infection efficiency of type 5 adenoviral vectors in synovial tissue can be enhanced with 2001 Mar OBJECTIVE: To obtain an adenoviral vector with increased infection efficiency in the synovial tissue compared with conventional vectors based on adenovirus serotype 5 (Ad5), without compromising the specificity of infection. METHODS: Coxsackie adenovirus receptor (CAR) expression was assessed in cultured synoviocytes. Chimeric adenoviruses based on Ad5 but carrying the DNA encoding the fiber of adenovirus from subgroup B (Adll, 16, 35) or D (Ad24, 28, 33, 45, or 47) were constructed and produced on PER.C6 cells. The gene transfer efficiency of these chimera was tested on cultured synoviocytes and peripheral blood mononuclear cells (PBMC). RESULTS: No surface expression of CAR protein was observed on synoviocytes. CAR messenger RNA expression of synoviocytes was found to be low. Of all fiber chimeric vectors tested, vectors carrying the fiber of Ad16 (Ad5.fib16) were most potent, yielding approximately150 times increased transgene expression in cultured synoviocytes compared with those of Ad5. Flow cytometry showed that the increase in transgene expression was caused by the transduction of higher percentages of synoviocytes and higher gene expression per synoviocyte. Experiments with 500 virus particles/cell of Ad5.GFP or Ad5.fib16.GFP resulted in an infection efficiency of 0.6% and 1% in PBMC and 43% and 76% in synoviocytes, respectively. CONCLUSION: Synoviocytes hardly express CAR, which hampers Ad5-mediated gene transfer. Ad5.fib16 is superior to Ad5 vectors for transducing synoviocytes, without compromising the specificity of infection. Our data suggest that Ad5.fib16-mediated gene transfer to synovial tissue improves the therapeutic window.