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ID PMID Title PublicationDate abstract
15034063 CD14 is an acute-phase protein. 2004 Apr 1 The origin of soluble CD14 (sCD14) in the circulation is uncertain. To examine whether CD14 could be an acute-phase protein (APP), the levels of sCD14, IL-6, and C-reactive protein were determined by ELISA in serum and synovial fluid (SF) of patients with various arthropathies, and the regulation of CD14 synthesis was examined in liver cells. In patients with crystal-mediated or immunologically mediated arthritis (rheumatoid arthritis), serum levels of sCD14 were higher than or similar to those found in infection-mediated arthritis (reactive arthritis), precluding a relation with bacteria exposure. Levels of sCD14 were similar in SF and serum, and did not correlate with the number of SF leukocytes, excluding an important source from leukocyte membrane-bound CD14, by protease-mediated shedding. In contrast, serum levels of sCD14 in patients correlated with those of C-reactive protein, a classical APP, and IL-6, a cytokine known to regulate the synthesis of APP in the liver. Serum levels of sCD14 also correlated with disease activity in rheumatoid arthritis and reactive arthritis patients. IL-6 stimulated the production of CD14 by HepG2 hepatoma cells. By real-time PCR, the inducibility of CD14 by IL-6 was also observed at the mRNA level both in HepG2 cells and human primary hepatocytes. These in vitro results were confirmed by in vivo studies in IL-6(-/-) mice injected with turpentine, an experimental model of acute-phase response. Liver levels of CD14 mRNA increased in IL-6(+/+), but not in IL-6(-/-) mice. These results indicate that sCD14 can be considered as a type 2 APP.
11859737 [Chemoprevention of colorectal cancer]. 2002 Jan 26 A NEW CONCEPT: Chemoprevention of cancer consists in the administration of chemical agents to prevent or inhibit carcinogenesis. This strategy can be applied at any stage of carcinogenesis. ASSESSMENT: The development of such agents relies on classical bases: phases I, II and III. The approach consists in assessing the effect of the substance tested in patients with history of resected adenomas of the colon and at high risk of relapse and/or family risk of colon cancer. THE PRINCIPLE AGENTS UNDER ASSESSMENT: Are aspirin, type 2 cyclo-oxygenase inhibitors, calcium, folic acid, certain vitamins, hormone replacement therapy for menopausal women and difluoromethylornithine (DFMO).
12384915 CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis. 2002 Oct OBJECTIVE: CD14+,CD16+ monocytes, identified as a minor population of monocytes in human peripheral blood (PB), have been implicated in several inflammatory diseases. We undertook this study to investigate the relevance of this phenotype to joint inflammation in rheumatoid arthritis (RA). METHODS: The expression of CD14, CD16, CC chemokine receptor 1 (CCR1), CCR5, and intercellular adhesion molecule 1 (ICAM-1) on monocytes was measured by flow cytometric analysis. Concentrations of the cytokines known to induce CD16 (including transforming growth factor beta1 [TGFbeta1], macrophage colony-stimulating factor [M-CSF], and interleukin-10 [IL-10]) and concentrations of the soluble form of CD14 (sCD14) in plasma and synovial fluid (SF) samples were measured by enzyme-linked immunosorbent assay. The induction of CD16 on RA blood monocytes cultured for 18 hours with 1 or with all 3 cytokines was determined. RESULTS: The mean +/- SD frequency of CD14+,CD16+ blood monocytes was significantly increased in RA patients (11.7 +/- 5.6%; n = 105) compared with healthy controls (9.5 +/- 2.2%; n = 15) (P < 0.01), and the patient group with an increased frequency of CD16+ monocytes (> or =13.9%) had active disease, as defined by increased counts of tender and swollen joints, levels of acute-phase reactants, and titers of rheumatoid factor. The response to drug therapy correlated with changes in the frequency of this phenotype. The expression of CD16 on SF monocytes from RA patients was markedly elevated compared with the expression on PB monocytes. CD16 expression on RA blood monocytes was augmented in vitro by IL-10, M-CSF, and TGFbeta1. Plasma concentrations of these cytokines and of sCD14 were significantly higher in RA patients with high CD16+ monocyte frequencies than in those with low CD16+ monocyte frequencies or in healthy controls. CD14+,CD16+ monocytes expressed higher levels of CCR1, CCR5, and ICAM-1 than did regular CD14++,CD16- monocytes, particularly in active RA. CONCLUSION: These results indicate that the maturation of blood monocytes into tissue-infiltrative CD16+ cells before entry into the joint, induced by cytokine spillover from the inflamed joint, may contribute to the persistent joint inflammation of RA.
12425890 [Quantification of bone scintigraphy as an objective method in the follow-up of radioisoto 2002 Nov This work tries to provide the clinicians an objective tool that can contribute to the assessment of the results of radioisotopic synoviorthesis (RS). This study aims to assess the value of the quantification of bone scintigraphy in blood pool and late phase of the affected joints treated with 90Y silicate, in order to observe the clinical improvement experienced by most of these patients. A total of 69 bone scintigraphies (BS) in blood pool and late phase have been quantified. They belonged to 23 patients who were treated with RS with 90Y. The first scintigraphy study was performed before the treatment, the second and the third ones were performed 2 and 6 months after treatment. In each BS we quantified the index: counts per pixel of healthy / affected joint. We also have calculated the fraction in the late phase: counts per pixel of healthy bone / counts per pixel of affected and healthy joint. For the comparative statistical analysis of the results we used the Student's t test. We considered statistical significance when p < 0.05. All the patients presented clinical improvement. If we compare the index obtained in BS 2 months after treatment and pre-treatment we find statistical significance (p < 0.05) in the increase of index in the anterior view and late phase. If we compare the index obtained in BS 6 month after treatment and pre-treatment, we find a statistically significant increase in the anterior (p < 0.01) and posterior (p < 0.05) view of the blood pool phase and the anterior view of late phase (p < 0.01). The fraction counts per pixel of healthy bone / counts per pixel of affected and healthy joint did not present a significant increase in any BS control (2 and 6 months). We recommend quantification using the index (counts per pixel healthy / affected joint ) proposed in this work, because it is easy to perform, cheap and reliable in the follow-up of patients treated with RS.
15345128 Impact of leukapheresis cell composition on immunomagnetic cell selection with the Baxter 2004 Aug Immunomagnetic cell selection (ICS) of CD34(+) cells is increasingly adopted in allogeneic and autologous transplant settings. Because many variables can affect the final results of ICS, we focused our study toward the influence exerted by the leukapheresis (LKF) cell composition on recovery, purity, and log of T and B depletion of the immunoselected cells. A total of 39 consecutive CD34(+) ICS were performed with the Isolex 300i (Baxter) device on 39 LKF from 9 HLA haploidentical donors and 20 patients. Flow cytometric analysis was performed both on the leukapheresis content and on the immunoselected cells. The statistical analysis was performed utilizing the Pearson's correlation test and the Mann-Whitney U test. The median purity and recovery of the immunoselected CD34(+) cells were 95.3% (IR: 93.0-99.0) and 55.1% (IR: 41.8-68.2), respectively. The median log of T and B depletion were 3.87 (IR: 3.5-4.3) and 2.9 (IR: 2.5-3.5), respectively. Our data indicate that not only the CD34(+) cell load but also the ratio among the cells belonging to the starting fraction can influence the results of ICS. LKF collection protocols have to be addressed to collect an high number of CD34(+) cells (>500 x 10(6)) without taking care of the contaminating cells when the Baxter Isolex 300i device is employed.
12180737 Interleukin 17 induced nitric oxide suppresses matrix synthesis and protects cartilage fro 2002 Aug OBJECTIVE: To investigate the role of nitric oxide (NO) in basal and cytokine induced cartilage matrix breakdown and synthesis across different species and in chondrocytes cultured as isolated cells or as tissue explants. METHODS: Articular cartilage from bovine, porcine, or human joints was cultured as explants in serum-free media. Explants or monolayer cultures of primary chondrocytes were treated with cytokines in the absence or presence of inhibitors [antibodies to leukemia inhibitory factor (anti-LIF) or tumor necrosis factor-alpha, dexamethasone, or inhibitors of aggrecanase or NO synthase]. NO production and matrix breakdown and synthesis were measured. RESULTS: At low concentrations, a novel interleukin 17 (IL-17) family member induced matrix breakdown without altering NO production. Treatment of articular cartilage explants with dexamethasone or anti-LIF blocked NO production by IL-17, but not by IL-1alpha. Inhibition of NO production in cytokine treated cartilage explants enhanced matrix breakdown and partially overcame suppression of matrix synthesis. In isolated chondrocytes, inhibition of NO production decreased expression of gelatinase and increased expression of stromelysin. CONCLUSION: Endogenous NO serves a dual function in cartilage: to protect the tissue from matrix breakdown and to mediate suppression of proteoglycan synthesis by cytokines. Despite the similarities in biological function between IL-I and IL-17, their downstream signaling pathways are distinct and appear to be affected by extracellular matrix degradation.
14978079 The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock prote 2004 Mar 1 Immunization of Lewis rats with heat-killed Mycobacterium tuberculosis H37Ra leads to development of polyarthritis (adjuvant-induced arthritis; AA) that shares several features with human rheumatoid arthritis (RA). Immune response to the 65-kDa mycobacterial heat-shock protein (Bhsp65) is believed to be involved in induction of AA as well as in experimental modulation of this disease. However, the understanding of several critical aspects of the pathogenesis of AA in the Lewis rat has severely been hampered by the lack of information both regarding the level as well as epitope specificity of tolerance to the mammalian self (rat) homologue of Bhsp65, 65-kDa rat heat-shock protein (Rhsp65), and about the functional attributes of the T cell repertoire specific for this self protein. In this study, we established that tolerance to Rhsp65 in the Lewis rat is incomplete, and that the residual T cells primed upon challenge with this self hsp65 are disease regulating in nature. We also have defined the T cell epitopes in the C-terminal region within Rhsp65 that contribute predominantly to the immune reactivity as well as the AA-protective effect of this self protein. Furthermore, the T cells primed by peptides comprising these C-terminal determinants can be efficiently restimulated by the naturally generated epitopes from endogenous Rhsp65, suggesting that self hsp65 might also be involved in natural remission from acute AA. These novel first experimental insights into the self hsp65-directed regulatory T cell repertoire in AA would help develop better immunotherapeutic approaches for autoimmune arthritis.
15124245 Increase of cyclooxygenase-2 expression by interleukin 15 in rheumatoid synoviocytes. 2004 May OBJECTIVE: To determine the effect of interleukin 15 (IL-15) on cyclooxygenase-2 (COX-2) expression in rheumatoid synoviocytes. METHODS: Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis (RA) and cultured in the presence of IL-15. Levels of COX-2 mRNA and protein expression were determined by reverse transcription-polymerase chain reaction and Western blot, respectively. ELISA was used to measure concentrations of IL-1beta, tumor necrosis factor-a (TNF-a), and prostaglandin E2 (PGE2) in the culture supernatants. RESULTS: IL-15 dose-dependently increased COX-2 mRNA and protein expression in FLS, but not the COX-1 mRNA level. Both IL-1beta and TNF-a upregulated COX-2 mRNA comparably to IL-15, but neither IL-2 nor interferon-g had any effect on the COX-2 mRNA level. Treatment with anti-IL-1beta or anti-TNF-a antibodies partially reduced the IL-15-stimulated COX-2 mRNA expression, suggesting that these cytokines may take part in modulating COX-2 by IL-15. Dexamethasone and pyrolidine dithiocarbamate, but not curcumin, completely blocked the IL-15-induced upregulation of COX-2 mRNA. A gel mobility shift assay revealed that nuclear factor-kB (NF-kB) was one of the major signal molecules to mediate IL-15-induced COX-2 upregulation. The increase of COX-2 by IL-15 is PGE2-dependent because exogenous PGE2 reversed the suppressive effect of NS-398, a selective COX-2 inhibitor, on COX-2 mRNA and protein expression. CONCLUSION: This study confirms the effect of IL-15 on upregulation of COX-2 in a PGE2-dependent manner. The activation of NF-kB bound to the COX-2 promoter appears to be a downstream target of IL-15 stimulation in FLS, exerted either directly or through the increase in IL-1beta and TNF-a production.
15528382 CD56bright NK cells are enriched at inflammatory sites and can engage with monocytes in a 2004 Nov 15 Human NK cells may be divided into a CD56(dim) subset and a CD56(bright) subset. In peripheral blood, CD56(dim) NK cells dominate, whereas in lymph nodes, CD56(bright) NK cells are more common. In this study we show that CD56(bright) NK cells accumulate within inflammatory lesions in a wide variety of clinical diseases affecting several different anatomical sites. We demonstrate that when activated by the monokines IL-12, IL-15, and IL-18, these NK cells promote TNF-alpha production by CD14(+) monocytes in a manner that is dependent on cell:cell contact. Conversely, CD14(+) monocytes synergize with monokines to promote IFN-gamma production by these NK cells. Again, this interaction is dependent on cell:cell contact. The experiments show that CD56(bright) NK cells accumulate in inflammatory lesions and, in the appropriate cytokine environment, can engage with CD14(+) monocytes in a reciprocal activatory fashion, thereby amplifying the inflammatory response. Such a positive feedback loop is likely to be important in the pathogenesis of chronic inflammatory conditions such as rheumatoid arthritis.
11965597 Agranulocytosis in Sjögren's syndrome: two case reports and analysis of 11 additional rep 2002 Apr OBJECTIVES: To report 2 patients who presented with agranulocytosis that was found to be immune-mediated and associated with occult primary Sjögren's syndrome (primary SS) and to identify and study similar cases reported in the literature. METHODS: Two patients encountered in 2 large medical centers over a period of 5 years were studied in detail. All reported cases of agranulocytosis in primary SS identified through a MEDLINE search were reviewed. RESULTS: Two patients presented with marked systemic symptoms alone or associated with recurrent infections. Agranulocytosis with either a pattern of maturation arrest or a hypercellular reactive bone marrow was found and was associated with "acute phase" markers, hypergammaglobulinemia, a small paraprotein peak, and high rheumatoid factor titers. A diagnosis of immune-mediated agranulocytosis associated with an occult primary SS was established and was successfully treated with intravenous immunoglobulins or prednisone. Both patients subsequently developed skin vasculitis. This rare association of agranulocytosis and Sjögren's syndrome was identified in 11 other cases and was the presenting manifestation of primary SS in 10 of 13 (77%) patients. CONCLUSIONS: Agranulocytosis should be recognized as a rare but well-established association of primary SS. Bone marrow neutrophil production may be affected, or neutrophils may be destroyed in the circulation, by both humoral and cellular immune-mediated mechanisms. Agranulocytosis or neutropenia should be added to the varied hematologic manifestations of primary SS and may be its presenting feature and an important clue to diagnosis.
12509619 The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E 2003 Jan OBJECTIVES: To investigate the effects of the active metabolite of leflunomide, A77 1726, on fibroblast-like synoviocytes. In rheumatoid arthritis (RA) synoviocytes participate in tissue destruction by producing metalloproteinases (MMP), prostaglandin E(2) (PGE(2)) and interleukin (IL) 6, which are involved in extracellular matrix degradation, resorption of the mineral phase and osteoclast-mediated bone resorption. METHODS: Human synoviocytes were stimulated with IL-1alpha or tumour necrosis factor alpha (TNF-alpha) in the presence of A77 1726. Culture supernatants were analysed for production of interstitial collagenase (MMP-1), tissue-inhibitor of metalloproteinases 1 (TIMP-1), PGE(2) and IL-6. Total RNA was isolated and analysed for steady-state levels of MMP-1, cyclooxygenase-2 (COX-2) and IL-6 mRNA. RESULTS: A77 1726 inhibited the production of PGE(2) in synoviocytes activated by TNF-alpha and IL-1alpha with median inhibitory concentrations (IC(50)) of 7 and 3 microM respectively. In contrast, MMP-1 and IL-6 production was inhibited at high A77 1726 concentrations (> 10 microM), whereas TIMP-1 was not affected. The inhibition of MMP-1 and IL-6 production was due to the known inhibitory effect of A77 1726 on pyrimidine synthesis, as it was reversed by the addition of uridine. This did not apply to PGE(2) production, which was inhibited via direct action of A77 1726 on COX-2, as shown by the increasing amount of substrate (arachidonic acid) in the culture medium. CONCLUSION: This study shows that some of the beneficial effect of leflunomide in RA patients may be due to the inhibition of PGE(2), IL-6 and MMP-1 production in synoviocytes. This effect, coupled with its multiple inhibitory effects on T lymphocyte functions, might account for the significant reduction in the rate of disease progression in RA patients treated with leflunomide.
12787513 Laboratory assessment in musculoskeletal disorders. 2003 Jun Autoimmune-mediated musculoskeletal disorders feature the presence and pathogenic role of circulating autoantibodies and autoreactive T cells. Determination of these autoantibodies provides crucial information to establish the diagnosis of these diseases. In addition, the determination of these antibodies may have prognostic value or may be used to monitor response to treatment or to predict relapse of disease. We first address the main characteristics of several autoantibody assays that are considered to be clinically most relevant. These include rheumatoid factor (RF), anti-cyclic citrullinated antibody (anti-CCP), antinuclear autoantibodies (ANA), anti-double-stranded DNA antibodies, antibodies to extractable nuclear antigens (ENA), and antineutrophil cytoplasmic autoantibodies (ANCA). Subsequently we provide a brief overview of the most important musculoskeletal disorders, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis/CREST, polymyositis/dermatomyositis and vasculitis. Our main goal was to address the role of the determination of autoantibodies in the diagnosis and follow-up of musculoskeletal disorders.
15347439 [Clinical features of primary Sjögren's syndrome in childhood]. 2004 Aug OBJECTIVE: To assess the clinical features of primary Sjgren's syndrome (pSS) in childhood and adult patients to understand the differences between them. METHOD: Data of 21 childhood and 400 adult patients with definite primary Sjgren's syndrome were analyzed retrospectively. RESULTS: In adult patients, initial clinical symptoms were various, dry mouth and dry eyes, arthritis and arthralgia, parotid swelling, renal tubular abnormalities (RTA) were more common. Compared with adult patients, RTA, parotid swelling and rash were more common in childhood, pulmonary abnormalities and neurologic system involvement were less common. The frequency of renal tubular abnormalities (52.4%) and rash (47.6%) in childhood pSS were higher than those of adults, but the frequencies of dry eyes (61.0%) and pulmonary interstitial fibrosis (25.2%) in adults pSS were higher than those in childhood (P < 0.01); serum rheumatoid factor (RF) and gamma-globulin were higher in all childhood patients (P < 0.01). Anti-nuclear antibody (ANA), anti-SSA and anti-SSB antibodies, and IgG were significantly higher in childhood cases than in adult patients (P < 0.05 or 0.01). CONCLUSION: The major clinical characteristics of childhood pSS cases included: (1) RTA, parotid swelling and rash which appeared earlier, but dry mouth and dry eyes appeared later and were mild. (2) The frequency of pulmonary abnormalities, nervous system involvement and Raynaud's phenomenon were less commonly seen. (3) Positivity of RF, anti-SSA and anti-SSB antibodies, and serum IgG were higher.
12946237 Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. 2003 Aug One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and T-helper 2 (Th2) activity. The Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells expressed differing cytokine patterns. This hypothesis was adapted to human immunity, with Th1- and Th2-helper cells directing different immune response pathways. Th1 cells drive the type-1 pathway ("cellular immunity") to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive the type-2 pathway ("humoral immunity") and up-regulate antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy. Overactivation of either pattern can cause disease, and either pathway can down-regulate the other. But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro-Th1 or -Th2 patterns. The non-helper regulatory T cells, or the antigen-presenting cells (APC), likely influence immunity in a manner comparable to Th1 and Th2 cells. Many diseases previously classified as Th1 or Th2 dominant fail to meet the set criteria. Experimentally, Th1 polarization is readily transformed to Th2 dominance through depletion of intracellular glutathione, and vice versa. Mercury depletes glutathione and polarizes toward Th2 dominance. Several nutrients and hormones measurably influence Th1/Th2 balance, including plant sterols/sterolins, melatonin, probiotics, progesterone, and the minerals selenium and zinc. The long-chain omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect. Th1/Th2-based immunotherapies, e.g., T-cell receptor (TCR) peptides and interleukin-4 (IL-4) injections, have produced mixed results to date.
12198000 Flavonoid intake and risk of chronic diseases. 2002 Sep BACKGROUND: Flavonoids are effective antioxidants and may protect against several chronic diseases. OBJECTIVE: The association between flavonoid intake and risk of several chronic diseases was studied. DESIGN: The total dietary intakes of 10 054 men and women during the year preceding the baseline examination were determined with a dietary history method. Flavonoid intakes were estimated, mainly on the basis of the flavonoid concentrations in Finnish foods. The incident cases of the diseases considered were identified from different national public health registers. RESULTS: Persons with higher quercetin intakes had lower mortality from ischemic heart disease. The relative risk (RR) between the highest and lowest quartiles was 0.79 (95% CI: 0.63, 0.99: P for trend = 0.02). The incidence of cerebrovascular disease was lower at higher kaempferol (0.70; 0.56, 0.86; P = 0.003), naringenin (0.79; 0.64, 0.98; P = 0.06), and hesperetin (0.80; 0.64, 0.99; P = 0.008) intakes. Men with higher quercetin intakes had a lower lung cancer incidence (0.42; 0.25, 0.72; P = 0.001), and men with higher myricetin intakes had a lower prostate cancer risk (0.43; 0.22, 0.86; P = 0.002). Asthma incidence was lower at higher quercetin (0.76; 0.56, 1.01; P = 0.005), naringenin (0.69; 0.50, 0.94; P = 0.06), and hesperetin (0.64; 0.46, 0.88; P = 0.03) intakes. A trend toward a reduction in risk of type 2 diabetes was associated with higher quercetin (0.81; 0.64, 1.02; P = 0.07) and myricetin (0.79; 0.62, 1.00; P = 0.07) intakes. CONCLUSION: The risk of some chronic diseases may be lower at higher dietary flavonoid intakes.
12519300 Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a fu 2003 Jan MUC1 is a transmembrane mucin that is expressed on ductal epithelial cells and epithelial malignancies and has been proposed as a target antigen for immunotherapy. The expression of MUC1 has recently been reported on T and B cells. In this study we demonstrate that following activation in vivo or activation by different stimuli in vitro, human T cells expressed MUC1 at the cell surface. However, the level of expression in activated human T cells was significantly lower than that seen on normal epithelial cells or on breast cancer cells. In contrast, resting T cells did not bind MUC1-specific monoclonal antibodies (mAbs), nor was MUC1 mRNA detectable by reverse transcription-polymerase chain reaction (RT-PCR) or Northern blot analysis in these cells. The profile of activated T-cell reactivity with different MUC1-specific antibodies suggested that the glycoform of MUC1 expressed by the activated T cells carried core 2-based O-glycans, as opposed to the core 1 structures that dominate in the cancer-associated mucin. Confocal microscopy revealed that MUC1 was uniformly distributed on the surface of activated T cells. However, when the cells were polarized in response to a migratory chemokine, MUC1 was found on the leading edge rather than on the uropod, where other large mucin-like molecules on T cells are trafficked. The concentration of MUC1 at the leading edge of polarized activated human T cells suggests that MUC1 could be involved in early interactions between T cells and endothelial cells at inflammatory sites.
12055982 The hypothalamic-pituitary-adrenal axis in the pathogenesis of rheumatic diseases. 2002 Mar Many studies have demonstrated altered HPA axis activity in patients with rheumatic diseases. In the case of autoimmune inflammatory diseases, circumstantial evidence suggests that failure of the neuroendocrine-immune regulatory loop may lead to insufficient production of endogenous glucocorticoid. Nevertheless, in human autoimmune disease, it is not possible to determine if altered HPA axis activity predates the onset of chronic inflammation. Animal studies and some early genetic studies in RA patients lend credibility to the argument that insufficient HPA axis response to inflammatory stimuli may increase susceptibility to, or severity of, these diseases. Most patients with rheumatic diseases complain of musculoskeletal pain. There is evidence of HPA axis involvement in acute and chronic pain. In the case of FM, pain cannot be explained on the basis of inflammation or altered musculoskeletal anatomy. This has led to the hypothesis that central nervous system mechanisms contribute to the symptom of somatic pain. Again, it is unclear if the observed HPA axis abnormalities reflect pre-existing vulnerability to the FM spectrum of disease, or whether chronic somatic symptoms alter HPA axis activity. Availability of technology to study better central components of the HPA axis may shed further light on its role in the pathogenesis of inflammatory autoimmune rheumatic diseases and musculoskeletal pain syndromes.
11835133 Electrochemical monitoring of cell behaviour in vitro: a new technology. 2002 Mar 30 This article describes a novel electrochemical technique for the real-time monitoring of changes in the behaviour of adherent human cells in vitro: i.e., a biosensor that combines a biological recognition mechanism with a physical transduction technique, described collectively as Oncoprobe. Confluent viable cells adherent to gold electrodes (sensors) modify the extracellular microenvironment at the cell:sensor interface to produce a change in the electrochemical potential compared to that measured in the absence of cells. The potential was measured as an open circuit potential (OCP) with respect to a saturated calomel reference in the bulk culture medium. Typical OCP values for confluent cultures of human breast carcinoma cells, 8701-BC, approximated -100 mV compared with cell-free values of approximately -15 mV. The OCP for 8701-BC cells was modified in response to temperature changes over the range 32 to 40 degrees C and also to treatments with phytohemagglutinin (PHA, 25 microg/mL), cycloheximide (30 microM) and interleukin-1 beta (IL-1, 0.5 ng/mL) over 24 h. Cultures of synovial fibroblasts also responded to the same treatments with similar responses, producing negative shifts in the OCP signal with PHA and IL-I, but a positive shift in OCP signal with cycloheximide, all relative to the untreated control cultures. From experimental data and theoretical considerations it is proposed that the cell-derived signals are mixed electrode potentials reflecting a "conditioned," more reducing environment at the cell:sensor interface. Only viable cells caused a negative shift in the OCP signal, this being lost when cells were rendered nonviable by formalin exposure. This technology appears unique in its ability to passively "listen in" on cell surface activities, suggesting numerous applications in the fields of drug discovery, chemotherapy, and cell behaviour.
15457463 Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and 2004 Sep OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in spondylarthropathy (SpA) synovitis. METHODS: Paired samples of synovial biopsy tissue as well as serum and synovial fluid (SF) from 41 patients with SpA and 20 patients with rheumatoid arthritis (RA) and serum samples from 20 healthy controls were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay for the presence of MMPs 1, 2, 3, and 9 and TIMPs 1 and 2. In addition, sera from 16 patients with ankylosing spondylitis (AS) and peripheral synovitis and 17 patients with AS and exclusively axial involvement were analyzed. An additional cohort of SpA patients was analyzed at baseline and after 12 weeks of infliximab treatment. RESULTS: Staining for MMPs and TIMPs showed a cellular and interstitial pattern in the synovial lining and sublining layers that was similar between the RA and SpA patients. Involvement of MMPs and TIMPs in SpA synovitis was suggested by the correlation with cellular infiltration, vascularization, and cartilage degradation. Higher serum levels of MMPs 3 and 9 were revealed in SpA and RA patients as compared with healthy controls. Production of MMP-3, but not MMP-9, in the serum reflected the presence of peripheral synovitis, as indicated by 1) the correlation between serum levels, SF levels (which were 1,000-fold higher than the serum levels), and synovial expression of MMP-3, 2) the increased levels of MMP-3 in AS patients with peripheral disease and not exclusively axial involvement, and 3) the correlation of serum and SF MMP-3 with parameters of synovial, but not systemic, inflammation. The modulation of the MMP/TIMP system by tumor necrosis factor alpha (TNFalpha) blockade was confirmed by the down-regulation of all MMPs and TIMPs in the synovium and a pronounced and rapid decrease of serum MMP-3. CONCLUSION: MMPs and TIMPs are highly expressed in SpA synovitis and mirror both the inflammatory and tissue-remodeling aspects of the local disease process. Serum MMP-3, originating from the inflamed joint, represents a valuable biomarker for peripheral synovitis. Modulation of the MMP/TIMP system by infliximab could contribute to the antiinflammatory and tissue-remodeling effects of TNFalpha blockade in SpA.
12969349 Vocal fold deposits in autoimmune disease--an unusual cause of hoarseness. 2003 Oct The objective of this study was to evaluate the symptoms and clinical characteristics in patients with autoimmune vocal fold deposits. Fourteen patients underwent videolaryngostroboscopic examination and voice recording. Eleven of the 14 patients underwent rheumatological examination. In all cases, endoscopic examination showed transverse white-yellow band lesions in the middle of the membranous portion of the vocal folds. In most cases, the lesions were bilateral but not exactly opposing each other. The most common voice characteristics were instability and intermittent aphonia. Inflammatory disease was present in 10 patients; five of these had rheumatoid arthritis (RA). No immunological signs common for all patients could be found. The histological examination was consistent with rheumatoid nodules. Vocal fold deposits, occurring most often in patients with RA, is an uncommon cause of hoarseness. Because the patients may have hoarseness as their primary symptom, it is important for otolaryngologists to be familiar with this disorder.