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ID PMID Title PublicationDate abstract
15239538 Hypothesis: an alternative pathway for the regulation of inflammation. 2004 Regulation of inflammation is a crucial event since its alteration, such as in sepsis and chronic autoimmune (i.e. rheumatoid arthritis, lupus erythematosus) or infectious diseases (i.e. tuberculosis, leprosy), determines severe tissue damage. Although there is a general consensus that regulation of inflammation results from a balance between proinflammatory and antiinflammatory pathways, we arrived at the conclusion that well known chemoattractants/proinflammatory molecules such as bacterial formyl peptides or immune complexes (IC), could induce, paradoxically, strong antiinflammatory effects. Thus, we demonstrated that N-formyl-methionyl-leucyl-phenylalanine (FMLP) exerted a drastic antiinflammatory effect, inhibiting the secretion of tumor necrosis alpha (TNF-alpha) induced by lipopolysaccharides, a potent TNF-alpha inducer. We also determined that in human neutrophils FMLP and IC induced the downregulation of receptors for the Fc portion of IgG (FcgammaRII and FcgammaRIIIB). Moreover, FMLP inhibited interferon gamma (IFN-gamma)-induced FcgammaRI expression and IC downregulate class II molecules of the major histocompatibility complex on monocytes. Part of these effects were mediated by the release of aspartic-, serin-, or metalloproteases. All these results favor the postulation of a new concept on the regulation of inflammation carried out through an alternative and non conventional pathway, in which a chemoattractant/proinflammatory agent could, under certain circumstances, act as an antiinflammatory molecule.
15169894 Diet-induced obesity and reduced skin cancer susceptibility in matrix metalloproteinase 19 2004 Jun Matrix metalloproteinase 19 (MMP-19) is a member of the MMP family of endopeptidases that, in contrast to most MMPs, is widely expressed in human tissues under normal quiescent conditions. MMP-19 has been found to be associated with ovulation and angiogenic processes and is deregulated in diverse pathological conditions such as rheumatoid arthritis and cancer. To gain further insights into the in vivo functions of this protease, we have generated mutant mice deficient in Mmp19. These mice are viable and fertile and do not display any obvious abnormalities. However, Mmp19-null mice develop a diet-induced obesity due to adipocyte hypertrophy and exhibit decreased susceptibility to skin tumors induced by chemical carcinogens. Based on these results, we suggest that this enzyme plays an in vivo role in some of the tissue remodeling events associated with adipogenesis, as well as in pathological processes such as tumor progression.
15132920 [Effect of overall alkali of Tongbiling on CD69 expression activated mouse T lymphocytes]. 2003 Jan AIM: To investigate the effect of overall alkali of Tongbiling(TBL) on CD69 expression on activated mouse T lymphocytes and its possible mechanism. METHODS: Phorbol 12,13-dibutyrate(PDB) or concanavalin (ConA) were added successively into mouse lymphocytic culture with various concentration of overall alkali TBL. After 24 hours, CD69 expression rate on mouse T lymphocytes activated with PDB or ConA was analyzed by flow cytometry. RESULTS: Overall alkali TBL could significantly down-regulate CD69 expression in a dose-dependent manner. CONCLUSION: Overall alkali TBL can significantly inhibit CD69 expression on activated mouse T lymphocytes. This study provided an experimental basis for application of overall alkali TBL to treatment of rheumatoid arthritis.
15075666 SR31747A: a peripheral sigma ligand with potent antitumor activities. 2004 Feb SR31747A is currently being evaluated in phase IIb clinical trials for prostate cancer treatment. The molecule is a peripheral sigma ligand that binds four proteins in human cells, i.e. SRBP-1, sigma-2, HSI and its relative SRBP-2. SR31747A is a dual agent with both immunomodulatory and antiproliferative activities. The molecule blocks proliferation of human and mouse lymphocytes, modulates the expression of pro- and anti-inflammatory cytokines, and was shown to protect animals in vivo against acute and chronic inflammatory conditions such as acute graft-versus-host reaction, lethality induced by staphylococcal enterotoxin B and lipopolysaccharide or rheumatoid arthritis. Besides these immunomodulatory activities, the molecule also inhibits the proliferation of various tumor cell lines in vitro in a time- and concentration-dependent manner. In vivo, SR31747A has potent antitumoral activity as demonstrated against mammary and prostatic tumoral cell lines injected into nude mice, where both tumor incidence and growth were decreased by more than 40% following daily SR31747A treatment at 25 mg/kg i.p. The recent literature on SR31747A in cancer is reviewed here. We focus specifically on preclinical data obtained in vivo and on studies aimed at deciphering the mode of action of the molecule.
15032640 T-cell-mediated signalling in immune, inflammatory and angiogenic processes: the cascade o 2004 Mar In the last decade, the understanding of the molecular mechanisms of regulation of the inflammatory process in chronic inflammatory diseases has moved remarkably forward. Recent evidence in various fields has consistently indicated that T-cells play a key role in initiating and perpetuating inflammation, not only via the production of soluble mediators but also via cell/cell contact interactions with a variety of cell types through membrane receptors and their ligands. Signalling through CD40 and CD40 ligand is a versatile pathway that is potently involved in all these processes. In this article, we review how T-cells become activated by dendritic cells or inflammatory cytokines, and how these T-cells activate, in turn, monocytes/macrophages, endothelial cells, smooth muscle cells and fibroblasts to produce pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-6), chemokines (interleukin-8, monocyte chemotactic protein-1), tissue factor, the main initiator of the coagulation cascade in vivo, and finally matrix metalloproteinases, responsible for tissue destruction. Moreover, we discuss how CD40 ligand at inflammatory sites stimulates fibroblasts and tissue monocyte/macrophage production of VEGF, leading to angiogenesis, which promotes and maintains the chronic inflammatory process. This cascade of events is discussed in the context of disease initiation/progression, with particular reference to atherosclerosis and rheumatoid arthritis, and to potential novel therapeutic targets for their treatment.
15023050 Use of a multiple-enzyme/multiple-reagent assay system to quantify activity levels in samp 2004 Mar 23 Matrix metalloproteinases (MMPs) are a family of enzymes that are up-regulated in many diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). Here we report on a novel technique that can be used to simultaneously measure activity levels for a panel of enzymes, such as the MMPs. The technique, termed the multiple-enzyme/multiple-reagent assay system (MEMRAS), relies on the use of reagents such as substrates with varying selectivity profiles against a group of enzymes. When reaction rates are measured by following a change in fluorescence with time, for mixtures of enzymes, an equation with unknown concentrations for each activity is generated for each reagent used. Simultaneously solving the set of equations leads to a solution for the unknown concentrations. We have applied this mathematical technique to measure activity levels for mixtures of MMPs such as collagenase 3 and gelatinase A. In addition, because we were most interested in determining collagenase 3 levels as a potential biological marker for OA, we developed highly selective substrates for this enzyme by using results found in previous bacteriophage substrate-mapping experiments. Some of the best substrates tested have specific activities for collagenase 3 that are 37,000-, 17,000-, 90-, and 200-fold selective over stromelysin 1, collagenase 1, and gelatinases A and B, respectively.
14993811 Polycyclic aromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibro 2004 Mar Rheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce proinflammatory cytokines, which is implicated in the pathogenesis of the disease. Among the cytokines, IL-1 is the critical mediator of the disease. When human fibroblast-like synoviocytes line, MH7A, was treated with 3-methylcholanthrene (3-MC), a polycyclic aromatic hydrocarbon (PAH), mRNA of IL-1beta was up-regulated. MH7A cells express functional aryl hydrocarbon receptor (AhR) as shown by 3-MC-inducible CYP1A1 mRNA expression. The effect of 3-MC was inhibited by alpha-napthoflavone, an AhR antagonist, indicating that the effect of 3-MC is mediated via AhR. Benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) also up-regulated mRNA level of IL-1beta in the cells via AhR. As PAHs are much contained in cigarette smoke, these findings provide the possible basis for epidemiological studies indicating a strong association between heavy cigarette smoking and outcome of RA.
14977534 Persistent and dormant tubercle bacilli and latent tuberculosis. 2004 May 1 Tubercle bacillus has remarkable ability to persist in the human host and has caused latent infection in one third of the world population. The current tuberculosis (TB) chemotherapy while effective in killing growing bacilli is largely ineffective in killing persistent or dormant bacilli, leading to prolonged therapy. There is considerable recent interest to study mechanisms of persistence and dormancy in mycobacteria. Meanwhile, there is also confusion about the use of terminology of dormant and persistent bacilli. Different models of mycobacterial persistence have been established. Various mycobacterial factors have recently been identified that may be involved in persistence or dormancy and resuscitation of dormant organisms. The phenotypic resistance to antituberculosis drugs in persistent and dormant bacilli presents a major challenge for effective control of the disease. The host immune system is critical in controlling latent TB infection from reactivation. A recent interesting observation is the reactivation of latent TB infection by anti-TNF-alpha antibody used as a treatment for rheumatoid arthritis and Crohn's disease. The role of psychoneuroendocrinological factors in TB, which is often ignored in the era of modern chemotherapy but could be important for controlling latent infection, is also briefly reviewed. There is recent interest to develop new TB drugs that target persistent and dormant bacilli and also immunotherapeutic agents that enhance chemotherapy and better control latent infection. The complex interaction between the bacteria, drugs, host and the environment underscores the need for a combined approach that incorporates chemotherapy, immunotherapeutic agents, improved socioeconomic, nutritional and even conducive psychological factors for more effective control of TB and latent TB.
14713405 Bone disease in pediatric rheumatologic disorders. 2004 Feb Children with rheumatic disorders have multiple risk factors for impaired bone health, including delayed growth and development, malnutrition, decreased weight-bearing activity, inflammation, and glucocorticoid therapy. The impact of rheumatic disease during childhood may be immediate, resulting in fragility fractures, or delayed, because of suboptimal peak bone mass accrual. Recent years have seen increased interest in the effects of pediatric rheumatic disorders on bone mineralization, such as juvenile rheumatoid arthritis, systemic lupus erythematosus, and juvenile dermatomyositis. This review outlines the expected gains in bone size and mass during childhood and adolescence, and summarizes the advantages and disadvantages of available technologies for the assessment of skeletal growth and fragility in children. The varied threats to bone health in pediatric rheumatic disorders are reviewed, with emphasis on recent insights into the molecular mechanisms of inflammation-induced bone resorption. The literature assessing bone deficits and risk factors for impaired bone health in pediatric rheumatic disorders is reviewed, with consideration of the strengths and limitations of prior studies. Finally, future research directions are proposed.
14713278 A comparison of in vitro bioassays to determine cellular glucocorticoid sensitivity. 2004 Jan An altered cellular glucocorticoid (GC) sensitivity is associated with several pathophysiological conditions such as asthma, diabetes, or rheumatoid arthritis. Several bioassays have been developed and employed to assess cellular GC sensitivity of peripheral blood mononuclear cells (PBMC), but correlations between these have rarely been investigated. We have compared four mitogen-based assays and an FK506 binding protein 51 (FKBP51) mRNA induction assay, using ten controls and a GC-resistant patient. The mitogen-based assays were performed using either diluted whole blood or isolated PBMC, and showed relatively large assay variations for the parameters maximal effect and half-maximal effect concentration. The FKBP51 assay showed smaller intra-assay and within-individual variation compared with the mitogen-based assays. The whole blood-based mitogen assays and the FKBP51 assay clearly discriminated the GC-resistant patient from the controls but, in contrast to expectations, both PBMC-based mitogen assays did not. The GC-induced FKBP51 mRNA increase in PBMC may be an alternative to determine an altered individual GC sensitivity with several advantages as compared with mitogen-based assays, such as the use of unstimulated PBMC, and a better intra- and inter-individual reproducibility.
14699978 Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis. 2004 A contributing role of neurogenic inflammation has provided a new dimension in understanding the pathogenesis of various cutaneous and systemic inflammatory diseases such as atopic dermatitis, urticaria, rheumatoid arthritis, ulcerative colitis and bronchial asthma. Several critical observations, such as (i) psoriasis resolves at sites of anaesthesia, (ii) neuropeptides are upregulated, and (iii) there is a marked proliferation of terminal cutaneous nerves in psoriatic plaques, encouraged us to search for a mechanism of neural influence in inflammation and inflammatory diseases. In immunohistochemical studies, we found that keratinocytes in lesional and nonlesional psoriatic tissue express high levels of nerve growth factor (NGF) and that there is a marked upregulation of NGF receptors, p75 neurotrophin receptor (p75NTR) and tyrosine kinase A (TrkA), in the terminal cutaneous nerves of psoriatic lesions. As keratinocytes of psoriatic plaques express increased levels of NGF, it is likely that murine nerves will promptly proliferate into the transplanted plaques on a severe combined immunodeficient mouse. Indeed, we have noted marked proliferation of nerve fibers in transplanted psoriatic plaques compared with the few nerves in transplanted normal human skin. By double label immunofluorescence staining, we have further demonstrated that in these terminal cutaneous nerves there is a marked upregulation of neuropeptides, such as substance P and calcitonin gene-related protein. These observations, as well as recent findings about NGF-induced chemokine expression in keratinocytes, further substantiate a role of the NGF-p75NTR-TrkA system in the inflammatory process of psoriasis. Currently, we are evaluating antagonists to selected neuropeptides and NGF/receptors, with the expectation of identifying pharmacological agents to counter neurogenic inflammation in psoriasis.
14614765 Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. 2003 Tumour necrosis factor (TNF)-alpha is a potent cytokine involved in the inflammatory reactions of many acute and chronic diseases. Recently, agents that block TNFalpha either directly or indirectly have been successful in the treatment of a variety of immune-mediated inflammatory disorders including rheumatoid arthritis and Crohn's disease. Sarcoidosis is an immune-mediated inflammatory disorder characterised by the formation of granulomas. TNFalpha is important in the initiation and perpetuation of inflammation in sarcoidosis, contributing to the initiation of granulomas and the progression of fibrosis, as well as to nongranulomatous inflammation. Various agents used to treat sarcoidosis affect TNF, including the most widely used drug class, corticosteroids, which are usually effective in blocking TNFalpha release from cells. Other agents that nonspecifically inhibit TNFalpha release include methotrexate, azathioprine and pentoxifylline. Specific TNF-antagonising biological agents such as infliximab and etanercept are being tested in patients with sarcoidosis, with mixed success. Infliximab has been shown to produce clinical improvement and reduce the requirement for corticosteroids in a small number of patients with sarcoidosis. However, as infliximab can be associated with reactivation of tuberculosis, which could be mistaken as worsening sarcoidosis, it should be used with caution in this patient group.
14602848 Parent and child reporting of negative life events: discrepancy and agreement across pedia 2003 Dec OBJECTIVE: To examine the consistency in child and parent reporting of child's negative life events across child/pediatric samples. METHODS: A total of 613 child-parent dyads provided independent reports of negative life events. The pairs included three groups consisting of children who were healthy (n = 362), diagnosed with cancer (n = 130), and diagnosed with a chronic illness (juvenile rheumatoid arthritis, diabetes, or cystic fibrosis; n = 121). RESULTS: Children reported significantly more negative life events than their parents reported for them. Additionally, children in the chronically ill group self-reported significantly fewer negative life events than the other groups. However, parents of children with cancer reported significantly more negative life events than the other groups. Although discrepancies exist in all three samples, parents and children in the healthy group were significantly more discrepant than the other groups. CONCLUSIONS: These results suggest that communication of children's life events between parent and child may increase during children's experience of cancer or a chronic illness. However, significant discrepancies remain in child and parent report of negative life events. Because of this, clinicians are encouraged to recognize the strengths and limitations of using multiple reporters in assessing negative life events in children.
14579522 Targeting I kappa B kinase for the treatment of inflammatory and other disorders. 2003 Sep The nuclear transcription factor NF kappa B plays a critical role in the pathogenesis of a number of human disorders, particularly those with an inflammatory component. Due to the fact that I kappa B kinase (IKK)-catalyzed phosphorylation of I kappa B proteins is an essential step in the signal-induced activation of NF kappa B, targeting this kinase represents a fascinating opportunity to develop novel therapeutics. In this review, the current understanding of the role of IKK/NF kappa B in disease processes will be discussed, along with evidence demonstrating that IKK inhibitors will be efficacious in disorders ranging from rheumatoid arthritis to cancer and diabetes. Potential mechanism-based toxicities will also be discussed.
14572604 The metabolism of sulindac enhances its scavenging activity against reactive oxygen and ni 2003 Nov 1 Sulindac is a sulfoxide prodrug that, in vivo, is converted to the metabolites sulindac sulfide and sulindac sulfone. It is therapeutically used as an anti-inflammatory and analgesic in the symptomatic treatment of acute and chronic rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In addition to its anti-inflammatory properties, sulindac and its metabolites have been shown to have an important role in the prevention of colonic carcinogenesis. Although the inhibition of prostaglandin synthesis constitutes the primary mechanism of action of sulindac, it is well known that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are implicated in the pathophysiology of inflammation and cancer. Thus, the aim of this study was to evaluate the scavenging activity of sulindac and its sulfone and sulfide metabolites for an array of ROS (HO*, O2(*-), and HOCl) and RNS (*NO and ONOO-) using in vitro systems. The results we obtained demonstrate that the metabolism of sulindac increases its scavenging activity for all RNS and ROS studied, notably with regard to the scavenging of HOCl. These effects may strongly contribute to the anti-inflammatory and anticarcinogenic efficacy that has been shown for sulindac.
12931802 Outcome of calf deep-vein thrombosis after total knee arthroplasty. 2003 Aug We investigated the outcome of deep-vein thrombosis (DVT) in the calf after total knee arthroplasty (TKA) in 48 patients (45 women and three men) by clinical assessment and venographic study between three and four years after surgery. The mean age of the patients was 67.2 +/- 7.7 years (52 to 85) and the mean follow-up was 42.6 +/- 2.7 months (38 to 48). The diagnosis was osteoarthritis in 47 patients and rheumatoid arthritis in one patient. There were 44 calf thrombi, four popliteal thrombi but no thrombi in the femoral or iliac regions. Of the 48 patients, 24 were clinically symptomatic and 24 were asymptomatic. Clinical examination was carried out on 41 patients, of whom 37 underwent ascending venography. Seven were evaluated by telephone interview. No patient had the symptoms or signs of recurrent DVT, venous insufficiency in the affected leg, or a history of pulmonary embolism. No patient had been treated for complications of their DVT. Thirty-six of the 37 venographic studies were negative for either old or new DVT in the affected leg. One patient had residual thrombi in the muscular branches of the veins. Our study shows that deep-vein thromboses in the calf after TKA disappear spontaneously with time. No patient developed a recurrent DVT, proximal propagation or embolisation. Treatment of DVT in the calf after TKA should be based on the severity of the symptoms during the immediate postoperative period.
12852719 TNF-alpha blockade and tuberculosis: better look before you leap. 2003 Apr According to several reports, the risk of active tuberculosis in patients who are latently infected with Mycobacterium tuberculosis is increased after treatment with tumour necrosis factor alpha (TNF)-blocking agents. These drugs have demonstrated effectiveness and are increasingly being used for treatment of several inflammatory diseases, including rheumatoid arthritis and Crohn's disease. Specialists prescribing TNF-blocking agents should be aware of the risk of tuberculosis and other infections, the unusual and severe clinical presentations and the available preventive measures. In this review, we will weigh currently available data on the risk of infection with intracellular pathogens and in particular tuberculosis in patients treated with TNF-blocking agents, discuss the role of TNF in the pathogenesis of tuberculosis and describe the risk profile of this complication. Awaiting further consensus protocols, a provisional flow chart is presented that is based on dinical parameters to provide a logical framework to reduce and minimise the risk of tuberculosis during TNF blockade.
12773629 Interleukin-10 therapy--review of a new approach. 2003 Jun Interleukin (IL)-10 is an important immunoregulatory cytokine produced by many cell populations. Its main biological function seems to be the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. However, very recent data suggest IL-10 also mediates immunostimulatory properties that help to eliminate infectious and noninfectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, in vitro and animal experiments suggest a major impact of IL-10 in inflammatory, malignant, and autoimmune diseases. So IL-10 overexpression was found in certain tumors as melanoma and several lymphomas and is considered to promote further tumor development. Systemic IL-10 release is a powerful tool of the central nervous system to prevent hyperinflammatory processes by activation of the neuro-endocrine axis following acute stress reactions. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been produced and is currently being tested in clinical trials. This includes rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and chronic hepatitis C. The results are heterogeneous. They give new insight into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.
12735666 Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis. 2003 May Inflammation is a hallmark in the pathogenesis of pulmonary destruction in cystic fibrosis (CF). There is no proven effective systemic anti-inflammatory treatment for CF patients with advanced pulmonary disease. Methotrexate (MTX) is known as an effective anti-inflammatory treatment in asthma and in juvenile rheumatoid arthritis. The question was: Is an improvement in pulmonary function achievable with low-dose MTX in patients with cystic fibrosis and advanced pulmonary disease.? METHODS: We treated five CF patients with advanced pulmonary disease, who deteriorated in spite of intensive conventional therapy on an individual basis with low-dose MTX. FEV1% and immunoglobulin G (IgG) serum levels were followed from the year before to the year after starting with MTX. RESULTS: In the year before starting with MTX, FEV1% decreased (median: 10% FEV1; range 9-15% FEV1; P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% FEV1; P<0.05). IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX. CONCLUSION: These preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients and supports the need for a controlled prospective study.
12559609 Antibodies to centromere antigens measured by an automated enzyme immunoassay. 2003 Feb BACKGROUND: Anticentromere antibodies (ACA) are frequently observed in patients with Raynaud's phenomenon and in the CREST syndrome, a subclass of systemic sclerosis. Likewise, ACA are also found in other autoimmune and non-autoimmune diseases. The objective of the present study was to evaluate the clinical utility of the measurement of antibodies to the best characterized centromere antigen (CENP-B) protein by an enzyme-linked immunosorbent assay (ELISA) that uses human recombinant CENP-B antigen and compare it with indirect immunofluorescence assay (IFA) on HEp-2 cells. METHODS: We have analyzed 128 sera samples from patients with the following diseases: systemic lupus erythematosus (SLE, n = 53), mixed connective tissue disease (n = 1), primary Sjögren syndrome (n = 10), primary Raynaud's phenomenon (n = 10), primary systemic sclerosis (n = 7), polymyositis/dermatomyositis (n = 3), rheumatoid arthritis (n = 9), cutaneous lupus (n = 5), primary biliary cirrhosis (n = 9), chronic autoimmune hepatitis (n = 5) and ANA-positive non-autoimmune diseases (n = 16). RESULTS: The ELISA evaluated shows a good concordance with IFA, with the advantage of being an automatable quantitative technique. CONCLUSIONS: Measurement of anticentromere antibodies by this ELISA using human recombinant antigen is a useful alternative for the autoimmune laboratory checking for diseases associated with anticentromere antibodies.