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ID PMID Title PublicationDate abstract
9753258 Nonsteroidal antiinflammatory drugs could reverse Helicobacter pylori-induced apoptosis an 1998 Sep It remains controversial whether the harmful effects of Helicobacter pylori (Hp) and nonsteroidal antiinflammatory drugs (NSAIDs) are additive. We studied the effects of Hp (virulent and nonvirulent strains) and NSAIDs, alone or in combination, on apoptosis and proliferation of gastric epithelial cells in nonulcer dyspepsia (NUD) patients. Forty-four (25 Hp-positive and 19 Hp-negative) consecutive Chinese NUD patients with rheumatoid arthritis who had taken continuously NSAIDs for more than three months were recruited for this study. Another 41 (20 Hp-positive and 21 Hp-negative) NUD patients not on any NSAIDs were included as controls. All patients underwent a gastroscopy examination and gastric biopsies. Hp infection was confirmed by CLOtest, anti-Hp ELISA, and [13C]urea breath test. The CagA status was determined by the anti-CagA antibody assay. The degree of gastritis, apoptosis, and proliferation indices were determined with H&E staining, terminal uridine deoxynucleotidyl nick end-labeling (TUNEL), and proliferating cell nuclear antigen (PCNA) immunostaining methods, respectively. A significantly higher apoptosis was observed in subjects who had Hp infection or had been consuming NSAIDs when compared with the controls. Unlike NSAID-treated subjects, patients with Hp infection were shown to have significantly enhanced cell proliferation. However, the increased apoptosis and proliferation in Hp-positive subjects were reversed by also taking NSAIDs. No correlation was found between apoptosis and proliferation in all the study groups. There was no association found between CagA expression or degree of gastritis with cell proliferation or apoptosis. It was demonstrated at the cellular level that NSAIDs could abrogate apoptosis or proliferation effects induced by Hp. Furthermore, the latter effects appeared not to be influenced by the virulent nature of the Hp strains.
9708370 Reliability and validity testing of the Michigan Hand Outcomes Questionnaire. 1998 Jul In this study, psychometric principles were used to develop an outcomes questionnaire capable of measuring health state domains important to patients with hand disorders. These domains were hypothesized to include (1) overall hand function, (2) activities of daily living (ADL), (3) pain, (4) work performance, (5) aesthetics, and (6) patient satisfaction with hand function. An initial pool of 100 questions was pilot-tested for clarity in 20 patients; following factor analysis, the number of questions was reduced to a 37-item Michigan Hand Outcomes Questionnaire (MHQ). The MHQ, along with the Short Form-12, a generic health status outcomes questionnaire, was then administered to 200 consecutive patients at a university-based hand surgery clinic and was subjected to reliability and validity testing. The mean time required to complete the questionnaire was 10 minutes (range, 7-20 minutes). Factor analysis supported the 6 hypothesized scales. Test-retest reliability using Spearman's correlation demonstrated substantial agreement, ranging from 0.81 for the aesthetics scale to 0.97 for the ADL scale. In testing for internal consistency, Cronbach's alphas ranged from 0.86 for the pain scale to 0.97 for the ADL scale (values >0.7 for Cronbach's alpha are considered a good internal consistency). Correlation between scales gave evidence of construct validity. In comparing similar scales in the MHQ and the Short Form-12, a moderate correlation (range, 0.54-0.79) for the ADL, work performance, and pain scales was found. In evaluating the discriminate validity of the aesthetics scale, a significant difference (p = .0012) was found between the aesthetics scores for patients with carpal tunnel syndrome and patients with rheumatoid arthritis. The MHQ is a reliable and valid instrument for measuring hand outcomes. It can be used in a clinic setting with minimal burden to patients. The questions in the MHQ have undergone rigorous psychometric testing, and the MHQ is a promising instrument for evaluation of outcomes following hand surgery.
9694048 Is a purified protein derivative skin test and subsequent antituberculous chemoprophylaxis 1998 Our objective was to determine whether a purified protein derivative (PPD) skin test and subsequent isoniazid administration to patients with systemic rheumatic disease, who react positively and are about to receive corticosteroids, is necessary. For this purpose, 451 unselected patients with systemic rheumatic diseases, such as rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, scleroderma, poly- and dermatomyositis, mixed connective tissue disease, eosinophilic fasciitis, systemic necrotising vasculitis and Behçet's disease, were observed over a 6-year period. All patients had been started on steroids after commencement of the study and had received the drug for at least 1 year by the end of the study. A chest X-ray was performed before entry, every 6 months for the first year and yearly thereafter. A PPD skin test had been performed in 40 patients by other physicians, but it was our policy to omit the test. We divided our patients into age groups by decades. Steroid dosage varied according to diagnosis and severity. An initial chest X-ray revealed old inactive tuberculosis in 65 patients. During the follow-up period, none of the patients exhibited clinical or radiological evidence of reactivations of tuberculosis. However, at least 184 of the patients would have had a positive PPD skin test reaction, if tested. This figure is derived from the results of several studies on Greek army recruits whose current ages correspond to those of our patients. In conclusion, our results suggest that screening with a PPD and isoniazid prophylaxis, with all the potential risks for those who test positive, may not be necessary in patients with systemic rheumatic disease who will receive steroids.
9396371 [Expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases 1997 Oct OBJECTIVE: Rapidly destructive coxarthropathy (RDC) is characterized by rapid destruction of hip joints, but its pathogenetic mechanism is still obscure. Matrix metalloproteinases (MMPs) are possibly one of the candidates concerning with this mechanism. We attempted histochemical investigation to demonstrate MMPs and tissue inhibitor of metalloproteinases (TIMPs) in joint tissues obtained from RDC patients to clarify their roles in the destruction mechanism. MATERIALS AND METHODS: Joint tissues including synovia and cartilage-bone tissues were obtained from RDC patients at total hip replacement (THR). After fixation with 4% paraformaldehyde, cartilage-bone tissues were partly decalcified. We performed histochemical study for paraffin sections of these tissues by using avidin-biotin method. Antibodies used in this study were monoclonal antibodies to MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, TIMP-1, TIMP-2 and polyclonal antibody to MMP-3. RESULTS: Histological feature of RDC was severe destruction of cartilage and bone by invasion of non-specific granulation tissues composed of many small vessels, macrophages and fibroblastic cells. At the same time, RDC showed apparently fewer lymphocytic cells in these granulation tissues compare with rheumatoid arthritis. MMP-2 and MMP-9 were expressed most demonstrably in synovia and destructive regions of femoral heads, especially in osteoclasts, macrophages, and fibroblastic cells, while MMP-1, MMP-3, were slightly expressed only in the superficial layer of synovia in limited cases. MMP-8, usually contained in neutrophils, was not present in RDC. On the other hand TIMP-1 and TIMP-2 were presented throughout the synovia and destructive regions of femoral heads including fibroblastic cells, macrophages, osteoblasts and osteocytes. CONCLUSION: Immunohistochemical study revealed obvious presence of MMP-2 and MMP-9 in synovia and destructive regions of femoral heads in RDC. Those evidence suggest that MMP-2 and MMP-9 share very important role in the destructive mechanism of RDC, possibly under imbalance between TIMPs.
9263143 Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial f 1997 Aug OBJECTIVE: To determine levels of soluble interleukin 6 receptor-alpha (sIL-6R alpha) in synovial fluid (SF) and serum from patients with different rheumatic diseases, and to analyze its cellular origin compared to IL-6. METHODS: IL-6 and sIL-6R alpha concentrations were measured in sera, SF, and culture supernatants of different cells types using specific sandwich ELISA. RESULTS: IL-6 levels were significantly higher (30 to 1000-fold) in SF than in sera, and higher in inflammatory arthropathies such as rheumatoid arthritis (RA), chondrocalcinosis, and gout than in osteoarthritis (OA). sIL-6R alpha levels in SF from patients with RA, gout, and chondrocalcinosis were also higher (24.7 +/- 7.5, 23.2 +/- 9.1, and 19.5 +/- 7.4 ng/ml, respectively) than in patients with OA (10.1 +/- 5 ng/ml), although the difference was distinctly smaller. In contrast, sIL-6R alpha concentrations did not differ significantly between the sera of healthy donors and patients. sIL-6R alpha levels were similar in SF and sera from inflammatory arthropathies, but lower in all osteoarthritic SF, compared to their corresponding serum. In contrast to IL-6, sIL-6R alpha was produced in high amounts by hepatocytes but not by structural cells of the joint (chondrocytes, synoviocytes, fibroblasts, and endothelial cells). Polymorphonuclear cells and mononuclear cells released intermediate levels. A significant correlation between sIL-6R alpha concentration and total number of leukocytes was observed in SF. CONCLUSION: Elevated levels of sIL-6R alpha were found in serum, likely to result from a marked release by hepatocytes in vitro. That levels are higher in inflammatory SF may be due in part to release by inflammatory cells in situ.
9171174 Radiological and anatomical evaluation of the atlantoaxial transarticular screw fixation t 1997 Jun Sixty-one patients treated with C1-2 transarticular screw fixation for spinal instability participated in a detailed clinical and radiological study to determine outcome and clarify potential hazards. The most common condition was rheumatoid arthritis (37 patients) followed by traumatic instability (15 patients). Twenty-one of these patients (one-third) underwent either surgical revision for a previously failed posterior fusion technique or a combined anteroposterior procedure. Eleven patients underwent transoral odontoidectomy and excision of the arch of C-1 prior to posterior surgery. No patient died, but there were five vertebral artery (VA) injuries and one temporary cranial nerve palsy. Screw malposition (14% of placements) was comparable to another large series reported by Grob, et al. There were five broken screws, and all were associated with incorrect placement. Anatomical measurements were made on 25 axis bones. In 20% the VA groove on one side was large enough to reduce the width of the C-2 pedicle, thus preventing the safe passage of a 3.5-mm diameter screw. In addition to the obvious dangers in patients with damaged or deficient atlantoaxial lateral mass, the following risk factors were identified in this series: 1) incomplete reduction prior to screw placement, accounting for two-thirds of screw complications and all five VA injuries; 2) previous transoral surgery with removal of the anterior tubercle or the arch of the atlas, thus obliterating an important fluoroscopic landmark; and 3) failure to appreciate the size of the VA in the axis pedicle and lateral mass. A low trajectory with screw placement below the atlas tubercle was found in patients with VA laceration. The technique that was associated with an 87% fusion rate requires detailed computerized tomography scanning prior to surgery, very careful attention to local anatomy, and nearly complete atlantoaxial reduction during surgery.
11594570 Interleukin-2 fusion toxin: targeted therapy for cutaneous T cell lymphoma. 2001 Sep The interleukin (IL)-2 receptor has proved an attractive target for T cell-directed therapies. Agents including monoclonal antibodies, single-chain antibody immunoconjugates, radioimmunoconjugates, and, most recently, ligand fusion toxins have demonstrated activity in vitro and in clinical trials in both hematologic malignancies and diseases characterized by proliferation of activated T cells, such as graft-versus-host disease. DAB389IL-2 (ONTAK) is a ligand fusion toxin consisting of the full-length sequence of the IL-2 gene genetically fused to the enzymatically active and translocating domains of diphtheria toxin. DAB389IL-2 and its predecessor, DAB486IL-2, have demonstrated activity in a variety of diseases, including cutaneous T cell lymphoma (CTCL), psoriasis, rheumatoid arthritis, and HIV infection. Further clinical development of IL-2 fusion toxins in CTCL and other hematopoietic malignancies is predicated on identification of the high-affinity IL-2 receptor complex on the malignant cells and on a better understanding of the biological determinants of cytotoxicity of these molecules in vivo.
11461663 Detection of superficial zone protein in human and animal body fluids by cross-species mon 2001 Jun In this report we describe the purification of human superficial zone protein (SZP), the generation of cross-species monoclonal antibodies (MAbs) and the detection of this protein in human and animal body fluids. Human SZPs, used as immunizing antigens, were purified either from culture media of human cartilage organ cultures or from human synovial fluids. The immunizing antigens were mixed with RIBI adjuvant in one of three forms: nonmodified SZP, superficial zone protein-keyhole limpet hemocyanin conjugate (SZP-KLH), or a mixture of superficial zone protein and hyaluronic acid (SZP-HA). A panel of MAbs including GW4.23, S6.79, S13.52, S13.233, and S17.109 were generated and characterized. Monoclonal antibody (MAb) S6.79, an IgG2b with K(D) 3.14 x 10(-9) M from SZP-KLH immunization, is of particular interest. It reacts strongly to a large molecular weight form of SZP in both enzyme-linked immunosorbent assay (ELISA) and Western blotting. It stains the most superficial layer of articular cartilage in immunohistochemistry, whereas the middle and deep zones of cartilage are not stained. When MAb S6.79 was applied to Western blots of human body fluids, a strong 345-kDa band was detected in samples of synovial fluid and weaker bands of similar size were detected in samples of plasma and serum. MAb S6.79 also showed cross-species immunoreactivity with SZP in samples of synovial fluids harvested from bovine, dog, guinea pig, and rabbit, as demonstrated by Western blotting and antibody absorption experiments. This cross-species MAb will be a useful tool in human and animal model studies for monitoring SZP levels and tissue distribution. It may help define the roles of SZP in normal articular joints and may be of diagnostic or prognostic value for the measurement of SZP in pathological conditions such as osteoarthritis, rheumatoid arthritis, and camptodactyly-arthropathy-coxa vara-pericarditis.
11377701 Regulation of IL-18 production by IFN gamma and PGE2 in mouse microglial cells: involvemen 2001 Jun 1 Interleukin (IL)-18, a recently identified proinflammatory cytokine, has been implicated in a variety of pathological conditions such as rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory liver injury. Microglial cells are the primary cellular source of IL-18 in the brain. Along with other inflammatory mediators in the central nervous system (CNS), IL-18 may play an important role in the pathogenesis of various neurodegenerative diseases. To understand how lymphokines and lipid mediators participate in the regulation of microglial IL-18 production, we assessed the effects of interferon (IFN)gamma, one of the major macrophage-activating lymphokines, and prostaglandin (PG)E(2), a lipid mediator produced in the brain, on IL-18 production and the expression of the IL-18 processing enzyme, caspase-1, in mouse microglial cells. IFNgamma increased lipopolysaccharide (LPS)-induced IL-18 production and caspase-1 expression, while PGE(2) inhibited LPS-induced IL-18 production. A similar pattern of IL-18 regulation by IFNgamma and PGE(2) was observed at the mRNA level. The regulation of microglial activation by IFNgamma and PGE(2) was accompanied by differential modulation of LPS-induced NF-kB activation. While IFNgamma enhanced LPS-induced NF-kB activation, PGE(2) suppressed its activation. These results indicate that IFNgamma and PGE(2) are the important regulators of proinflammatory microglial activation in CNS, and suggest the involvement of NF-kB pathway in these regulatory processes.
11313794 Efficacy of adenoviral TNF alpha antisense is enhanced by a macrophage specific promoter. 2001 Feb Macrophage-derived TNF alpha is a critical mediator of inflammation and destruction in diseases such as rheumatoid arthritis and Crohn's disease. These studies were undertaken to develop an effective adenovirus-based strategy to specifically suppress TNF alpha in primary human macrophages. A variety of promoters and LTRs were evaluated for effective expression in the macrophage cell line RAW 264.7. The CMV promoter and the Visna LTR were the most strongly expressed and were therefore used to drive the expression of TNF alpha antisense fragments. In transient transfection assays, the antisense fragment terminating at the 3' end of the first exon (216 bp) was superior to the others (70 and 750 bp), when expressed under the control of either the CMV promoter or the Visna LTR. Adenoviral vectors expressing the 216 bp TNF alpha antisense fragment, controlled by the CMV promoter or the Visna LTR, were both effective at suppressing LPS-induced TNF alpha secretion by primary human macrophages. However, the Visna LTR was more effective not only at suppressing LPS-induced TNF alpha secretion, but also IL-6, which is highly sensitive to TNF alpha secretion. These results demonstrate that effective, specific, suppression of TNF alpha in macrophages is possible, employing a directed antisense approach and a promoter system that is highly efficient in human macrophages.
10973277 Circulating human B cells that express surrogate light chains and edited receptors. 2000 Sep Immunoglobulin gene recombination can result in the assembly of self-reactive antibodies. Deletion, anergy or receptor editing normally silence B cells that produce these autoantibodies. Receptor editing is highly efficient in mouse B cells that carry pre-recombined autoantibody transgenes or gene "knock-ins". However, it has been difficult to identify cells that have edited receptors in unmanipulated mice and humans. To try to identify such cells we isolated and characterized B cells that coexpress surrogate and conventional light chains (V-preB+L+) from the blood of normal human donors. V-preB+L+ B cells express RAG mRNA, display an unusual heavy and light chain antibody repertoire consistent with antiself reactivity, and show evidence of receptor editing. These cells accumulate in the joints of patients with rheumatoid arthritis, consistent with a role for V-preB+L+ B cells and receptor editing in autoimmune disease.
11227046 The immunotherapeutic potential of melatonin. 2001 Mar The interaction between the brain and the immune system is essential for the adaptive response of an organism against environmental challenges. In this context, the pineal neurohormone melatonin (MEL) plays an important role. T-helper cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors. Activation of MEL receptors enhances the release of T-helper cell Type 1 (Th1) cytokines, such as gamma-interferon (gamma-IFN) and IL-2, as well as of novel opioid cytokines. MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Therefore, MEL has interesting immunotherapeutic potential in both viral and bacterial infections. MEL may also influence haemopoiesis either by stimulating haemopoietic cytokines, including opioids, or by directly affecting specific progenitor cells such as pre-B cells, monocytes and NK cells. MEL may thus be used to stimulate the immune response during viral and bacterial infections as well as to strengthen the immune reactivity as a prophylactic procedure. In both mice and cancer patients, the haemopoietic effect of MEL may diminish the toxicity associated with common chemotherapeutic protocols. Through its pro-inflammatory action, MEL may play an adverse role in autoimmune diseases. Rheumatoid arthritis patients have increased nocturnal plasma levels of MEL and their synovial macrophages respond to MEL with an increased production of IL-12 and nitric oxide (NO). In these patients, inhibition of MEL synthesis or use of MEL antagonists might have a therapeutic effect. In other diseases such as multiple sclerosis the role of MEL is controversial. However, the correct therapeutic use of MEL or MEL antagonists should be based on a complete understanding of their mechanism of action. It is not yet clear whether MEL acts only on Th1 cells or also on T-helper Type 2 cells (Th2). This is an important point as the Th1/Th2 balance is of crucial importance in the immune system homeostasis. Furthermore, MEL being the endocrine messenger of darkness, its endogenous synthesis depends on the photoperiod and shows seasonal variations. Similarly, the pharmacological effects of MEL might also be season-dependent. No information is available concerning this point. Therefore, studies are needed to investigate whether the immunotherapeutic effect of MEL changes with the alternating seasons.
11209755 Crystal structure of the caspase activator human granzyme B, a proteinase highly specific 2000 Dec Granzyme B is the prototypic member of the granzymes, a family of trypsin-like serine proteinases localized in the dense cytoplasmic granules of activated natural killer cells and cytotoxic T lymphocytes. Granzyme B directly triggers apoptosis in target cells by activating the caspase pathway, and has been implicated in the etiology of rheumatoid arthritis. Human granzyme B expressed in a baculovirus system has been crystallized without inhibitor and its structure has been determined to 3.1 A resolution, after considerably improving the diffraction power of the crystals by controlled humidity changes. The granzyme B structure reveals an overall fold similar to that found in cathepsin G and human chymase. The guanidinium group of Arg226, anchored at the back of the S1-specificity pocket, can form a salt bridge with the P1-Asp side chain of a bound peptide substrate. The architecture of the substrate binding site of granzyme B appears to be designed to accommodate and cleave hexapeptides such as the sequence Ile-Glu-Thr-Asp-/Ser-Gly present in the activation site of pro-caspase-3, a proven physiological substrate of granzyme B. These granzyme B crystals, with fully accessible active sites, are well suited for soaking with small synthetic inhibitors that might be used for a treatment of chronic inflammatory disorders.
11097207 In vitro and in vivo expression of interstitial collagenase/MMP-1 by human mast cells. 2000 Degradation of the extracellular matrix occurs under physiological and pathological conditions, thought to be principally mediated by a family of neutral proteolytic enzymes termed the matrix metalloproteinases (MMPs). The present study was initiated to determine whether mast cells have the ability to produce these proteases in diseased and normal human tissue. Immunohistochemistry and in situ hybridization was performed to localize interstitial collagenase protein and mRNA transcripts in diseased human tissue. The human mast cell line HMC-1 was cultured under serum free conditions, stimulated with phorbol mystrate acetate (PMA) and supernatants analyzed by Western blotting and zymography to determine the profile of secreted MMPs. The dog mast cell line BR, known to secrete gelatinolytic enzymes, was used in parallel studies. Total RNA was extracted and analyzed by RT-PCR for the expression of tissue inhibitors of MMP (TIMPs). Collagenase-1 protein and mRNA were expressed by tryptase and chymase positive human mast cells in all tissue analyzed. This proteinase was also detected in the cytoplasm and conditioned media of HMC-1 cells. PMA induced gelatinolytic activity in both mast cell lines examined. TIMP-1 immunoreactivity was detected and TIMP-1, and -2 (but not TIMP-3) mRNA transcripts were amplified from HMC-1 cells. This is the first demonstration of the expression of collagenase-1 by human mast cells in both inflamed and normal tissues, and by a human mast cell line. MMPs secreted by these cells could contribute to the extensive matrix lysis characteristic of diseases such as rheumatoid arthritis and inflammatory ocular disorders. Alternatively collagenase-1 production by mast cells may play a critical role in cell invasion and migration into sites of inflammation.
11096152 Circulating levels of matrix metalloproteinases MMP-3 and MMP-2 in renal transplant recipi 2000 Dec BACKGROUND: Chronic transplant nephropathy remains the major cause of graft loss after the first year post transplant, with the exception of death with functioning graft. The histological hallmark of chronic kidney rejection is progressive fibrosis in which extracellular matrix turnover plays an important role. This turnover is regulated by several systems of connective tissue proteases, the matrix metalloproteinases family being one of them. Every metalloproteinase exerts a different function over extracellular matrix proteins and can contribute to the pathogenesis of several diseases, such as rheumatoid arthritis and glomerulonephritis. The role of metalloproteinases in the pathogenesis of chronic transplant nephropathy and in kidney transplantation has not yet been addressed. METHODS: We measured the serum levels of proMMP-1, proMMP-2 and proMMP-3 by ELISA in 40 patients with chronic transplant nephropathy, 30 with acute rejection, 30 with stable graft function for a time equivalent to chronic transplant nephropathy, 30 with stable graft function for a time equivalent to acute rejection, and 30 healthy age-paired blood donors. RESULTS: Serum proMMP-2 and proMMP-3 were significantly higher in patients with chronic transplant nephropathy than in patients with acute rejection, stable graft function and healthy donors. The most striking finding was the significant positive correlation observed between serum levels of proMMP-3 and serum creatinine, and between circulating levels of proMMP-2 and proteinuria. Serum concentration of proMMP-1 was increased in patients with acute rejection compared with those with stable graft function and healthy donors. CONCLUSIONS: Serum proMMP-2 and proMMP-3 reflect the changes of glomerular and interstitial extracellular matrix in chronic transplant nephropathy, suggesting that they could play a role in the pathogenesis of this condition. Acute rejection is associated with increased levels of proMMP-1, which could be a reflection of the stimulation induced by a number of inflammatory cytokines produced in such a process.
10878723 Anti-telomere antibodies in systemic lupus erythematosus: a new ELISA test for anti-DNA wi 2000 BACKGROUND: Telomeric hexamer repeats (TTAGGG/CCCTAA)n are highly repetitive sequences of DNA. They cap the termini of eukaryotic chromosomes and stabilize them, preventing degradation or fusion. Anti ds-DNA is one of the most specific tests for systemic lupus erythematosus (SLE). Of related importance, a preliminary report has suggested that anti-telomere antibodies are also highly specific for the presence of SLE. METHODS: 220 patients with SLE, 79 with rheumatoid arthritis (RA), 54 with other rheumatic diseases and 99 healthy controls were tested for anti-telomere antibody as measured by enzyme immunoassay detecting 30- and 60-mer telomeric repeats (5-10 hexamers). 48 of the 220 SLE patients charts were abstracted for 90 separate clinical, laboratory and treatment parameters. Comparisons were made between SLE and non-SLE patients, and within the lupus group for telomere positivity and among the latter 48 patients for anti-DNA (Farr) levels and SLEDAI scores. RESULTS: Anti-telomere antibody was present in 48.6% of the overall SLE group (220), 71% of our cohort (48), 11% with primary Sjogren's (2/18), 7. 6% with RA (6/79) and 2% of normal controls (2/99) (P<0.001 comparing SLE to all other groups). In the 48 patient cohort, anti-telomere antibody was more sensitive than anti-dsDNA (Farr) (71% vs 50%), but did not correlate with other clinical parameters, SLEDAI scores, or other autoantibodies. CONCLUSIONS: The detection of anti-telomere antibody appears to be more sensitive and may be as specific as anti-dsDNA (Farr) in SLE. The detection of telomeric repeats may be as accurate as other anti-DNA assay methodologies and more specific for the presence of SLE. The immunogenic potential of telomere biology related to the pathogenesis and/or diagnosis of SLE deserves further investigation.
10850355 Antitumor effect of gold as revealed by growth suppression of cultured cancer cells. 1998 Jun Gold agents have been widely used for the treatment of rheumatoid arthritis. We studied the growth inhibiting effect of such an agent on malignant cells in vitro. HCT-15, AGS cells derived from a human malignancy, and Meth/A cells from a malignant lymphoma of Balb/C mice were cultured separately with gold agent at concentrations of 2 micrograms/ml. Four days after the cultures had been incubated in a 5% CO2 incubator at 37 degrees C, cell counts were made; and significance of differences was analyzed by Student's t test. Additionally, HCT-15 cells were cultured with gold for two days, and then the cells were analyzed by flow cytometry. The growth of HCT-15, AGS, and Meth/A cells was suppressed by gold. Fifty percent suppression was observed at a concentration between 50 micrograms/ml and 10 micrograms/ml for HCT-15 cells, between 125 micrograms/ml and 50 micrograms/ml for AGS cells, and between 125 micrograms/ml and 50 micrograms/ml for Meth/A cells. Fifty percent suppression of HCT-15 cell growth by cisplatinum was found between 50 micrograms/ml and 10 micrograms/ml. Flow cytometric findings showed a significant rise in the tetraploid peak, a mild rise in the resion between diploid and tetraploid peaks, and an increase in cells with a ploidy greater than four. These data suggest that gold blocks the S phase, G2 to M phase, and M phase as well. To observe the cytotoxicity of gold, each of 10 of 4 week-old Balb/C mice was injected s.c. at a dose of 10 mg/kg or 2 mg/kg every other day for a total of 3 injections, or was administered the gold at 30 mg/kg/day p.o. for 10 days. All mice were still alive after 20 days of observation. Cisplatinum at a dose of 10 mg/kg was also injected s.c. one time into each of 10 mice, and 60% of the animals died within 10 days after the injection.
10836522 Clinical associations and characterisation of antineutrophil cytoplasmic antibodies direct 2000 Bactericidal/permeability-increasing protein (BPI) and azurocidin (AZ) are recently described target antigens of antineutrophil cytoplasmic antibodies (ANCA). In this study, BPI-ANCA were demonstrated most often in patients with ulcerative colitis (36/92, 39%), Crohn's disease (17/66, 26%) and cystic fibrosis (11/14, 79%), but also in patients with rheumatoid arthritis (8/40, 20%), systemic lupus erythematosus (SLE) (111/65, 17%) and mixed connective tissue disease (4/18, 22%). BPI-ANCA were also common in sera containing antinuclear (ANA) (9/43, 21%) or antidouble-stranded (ds) DNA (7/28, 25%) antibodies. There was no increased frequency of abnormal alpha1-antitrypsin (alphal1AT) phenotypes in patients with BPI-ANCA, and BPI-ANCA were not more common in individuals with an abnormal phenotype. The predominant IgG subclasses were IgG1 and IgG3; IgA but not IgM was present. Both IgG and IgA BPI-ANCA were high affinity antibodies, and the affinity of IgG antibodies did not change with time in the sera tested. Four of the five sera (80%) containing BPI-ANCA did not bind to denatured, reduced BPI, suggesting that most BPI-ANCA recognised conformational epitopes. AZ-ANCA were demonstrated in 2/11 patients (18%) with Wegener's granulomatosis, 3/12 (25%) with cystic fibrosis and 3/14 (21%) with chronic active hepatitis. AZ-ANCA were present in 5/25 sera (25%) with ANA, but the levels were only marginally elevated. AZ-ANCA were uncommon in patients with inflammatory bowel and rheumatological diseases, and in sera containing other autoantibodies. Again, there was no association with abnormal alpha1-AT phenotypes. BPI represents a major ANCA target antigen in patients with rheumatological as well as inflammatory bowel disease and cystic fibrosis, but AZ-ANCA are uncommon.
10762021 COX-2 and colon cancer: potential targets for chemoprevention. 2000 Evidence derived from several lines of investigation suggest that prostaglandins, metabolites of arachidonic acid, play an important role in colon cancer development. Elevated prostaglandin levels are found in colon cancers and their precursor lesions, adenomatous polyps. Agents such as aspirin and NSAIDs, which inhibit the generation of these arachidonic acid metabolites, are associated with a decreased risk of developing or dying from colon cancer. Both the amount of the agent used and the duration of exposure seem to be important variables. In animals, NSAIDs are among the most potent agents discovered for the reduction of tumors in both genetic and carcinogen-induced models. Data from human trials also suggests that NSAIDs such as sulindac can reduce the size and number of polyps in individuals with familial adenomatous polyposis (FAP). In parallel with the above findings, it is now understood that at least two forms of the enzyme responsible for the metabolism of arachidonic acid exist. One of these forms, COX-1, is generally considered a constitutive form that is responsible for maintaining normal physiologic function. Inhibition of COX-1 leads to many of the clinically undesirable side effects associated with NSAID use. The other known form of the enzyme, COX-2, is an inducible form that is found in increased levels in inflammatory states and in many cancers and their associated pre-malignant lesions. Levels of COX-2 are increased by exposure to mitogens and growth factors. Agents that specifically inhibit COX-2 are now in clinical development and appear to be well-tolerated and effective for the treatment of osteoarthritis and rheumatoid arthritis. The potential for use of COX-2 specific NSAIDs in the prevention of colon cancer is suggested from the distribution of COX-2 in adenomatous polyps and colon cancer and the effectiveness of these agents in genetic and carcinogen-induced animal models of colon cancer. The development of these agents for the prevention of colon cancer will be discussed.
10606356 Antirheumatic effect of IDS 23, a stinging nettle leaf extract, on in vitro expression of 1999 Dec OBJECTIVE: Stinging nettle leaf extracts are registered in Germany for adjuvant therapy of rheumatic diseases. In a whole blood culture system the nettle extract IDS 23 (Rheuma-Hek) inhibited lipopolysaccharide stimulated monocyte cytokine expression, indicating an immunomodulating effect. We investigated the immunomodulating effects of IDS 23 on phytohemagglutinin (PHA) stimulated peripheral blood mononuclear cells (PBMC) in vitro. METHODS: Using commercial immunoassays the distinct cytokine patterns of Th1 and Th2 cells were determined. Interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) mRNA expression was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) with PHA stimulated PBMC. RESULTS: IDS 23 inhibited PHA stimulated production of Th1-specific IL-2 and IFN-gamma in PBMC culture (n = 10) in a dose dependent manner up to 50+/-32% and 77+/-14%, respectively. In contrast, IDS 23 stimulated the secretion of Th2-specific IL-4. The dose dependent inhibiting effect on IL-2 and IFN-gamma expression was also detected with RT-PCR, while the amount of actin-specific mRNA transcript was not modified by IDS 23. CONCLUSION: Our results suggest the effective ingredient of IDS 23 acts by mediating a switch in T helper cell derived cytokine patterns. IDS 23 may inhibit the inflammatory cascade in autoimmune diseases like rheumatoid arthritis.