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ID PMID Title PublicationDate abstract
16216008 Calmodulin is a critical regulator of osteoclastic differentiation, function, and survival 2006 Jan 1 Increased osteoclastic resorption and subsequent bone loss are common features of many debilitating diseases including osteoporosis, bone metastases, Paget's disease, and rheumatoid arthritis. While rapid progress has been made in elucidating the signaling pathways directing osteoclast differentiation and function, a comprehensive picture is far from complete. Here, we explore the role of the Ca(2+)-activated regulator calmodulin in osteoclastic differentiation, functional bone resorption, and apoptosis. During active bone resorption, calmodulin expression is increased, and calmodulin concentrates at the ruffled border, the organelle utilized for acid transport and bone dissolution. Pharmacologic inhibitors of calmodulin, several of which are already used clinically as anti-cancer and anti-psychotic agents, inhibit osteoclastic acid transport, suggesting their potential as bone-sparing drugs. Recent studies also implicate calmodulin in osteoclast apoptosis through a mechanism involving its direct interaction with the death receptor Fas. During osteoclastogenesis, RANKL-induction stimulates a rise in intracellular Ca2+, which in turn activates calmodulin and its downstream effectors. In particular, the Ca(2+)/calmodulin-dependent phosphatase calcineurin and its targets, the NFAT family of transcription factors, have been posited as the master regulators of osteoclastogenesis. However, recent in vivo and in vitro studies demonstrate that another Ca(2+)/calmodulin-regulated effector protein, CaMKII, is also involved. CaMKII(+/-) mutant mice have reduced osteoclast numbers, and CaMKII antagonists inhibit osteoclastogenesis in vitro. Furthermore, CaMKII is known to activate AP-1 transcription factors, which are also required for RANKL-induced osteoclast gene transcription, and recent findings suggest that CaMKII can down-regulate gp130, a cytokine receptor involved in bone remodeling and implicated in numerous osteo-articular diseases.
19218706 Angiogenic activity of sera from patients with systemic autoimmune diseases in relation to 2008 Dec Systemic autoimmune diseases, such as vasculitis and collagen diseases, are characterized by chronic inflammation. Mutual interrelationship between angiogenesis and chronic inflammation has already been demonstrated. The aim of the study was to examine the effect of sera from patients with systemic autoimmune diseases on angiogenesis induced by human mononuclear cells. The study population consisted of 43 patients with a systemic autoimmune disease associated with pulmonary manifestations, divided into three groups: 14 with Wegener's granulomatosis (WG), 13 with systemic sclerosis (SS), and 16 with collagen vascular diseases (CVD) such as rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis. The control group consisted of 15 healthy volunteers. Clinical status was evaluated using a questionnaire. Standard chest radiographs were performed in all patients. Pulmonary function tests were performed according to the ERS standards. An animal model of a leukocyte-induced angiogenesis assay was used as an angiogenic test. Sera from WG and CVD patients significantly stimulated angiogenesis compared with healthy subjects (P<0.001). On the other hand, sera from healthy donors exerted a proangiogenic effect compared with PBS. In contrast, sera from SS patients significantly (P<0.001) inhibited angiogenesis compared with sera from healthy subjects and PBS. Proangiogenic effect of sera from systemic diseases patients depended on radiological changes. No significant correlation between a degree of dyspnea or functional pulmonary tests and the number of new vessels or angiogenesis index was found. Sera from patients with systemic autoimmune diseases and healthy people constitute the source of mediators modulating angiogenesis. These modulatory effects differ depending on the disease entity.
19120275 STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset 2008 Dec In an effort to discover non-HLA genes affecting susceptibility to type 1 diabetes (T1D), we have investigated the association of polymorphisms in STAT4, an important signaling molecule of IL-12, gammaIFN, and IL-23, in a sample of 389 T1D patients and 152 nondiabetic controls in Korea. Four SNPs on chromosome 2q, which were recently found to be associated with rheumatoid arthritis, were examined for association and linkage disequilibrium. We found that neither alleles or genotypes among all four SNPs nor reconstructed haplotypes of the three SNPs within the same LD block (rs7574865, rs8179673, and rs10181656) were associated with susceptibility to T1D. When we stratified T1D patients into early-onset and late-onset subgroups on the basis of fewer or more than 7.8 years of age at diagnosis, however, the minor alleles of three SNPs (rs7574865, rs8179673, and rs10181656) showed a significant association with susceptibility to T1D in the early-onset subgroup (i.e., rs7574865, OR = 1.44 [1.03-2.01], P < 0.05), but not in the late-onset subgroup, suggesting that STAT4 is related to earlier development of T1D. The analysis of genotypes and haplotypes of the same SNPs (rs7574865, rs8179673, and rs10181656) showed very comparable degrees of risk for T1D. The age at diagnosis is lowest in the patients carrying the homozygotes of a minor allele, middle in the heterozygotes, and highest in the homozygotes of a major allele, suggesting the dosage effects of risk alleles on the age of onset of disease. Recognizing that only the early-onset cases might represent the true autoimmune T1D in Asian populations, we see that STAT4 alleles and haplotype might influence cytokine signaling and, therefore, development of T1D.
18992278 Increased bone resorption and osteopenia are a part of the lymphoproliferative phenotype o 2008 Dec 22 Mice with interleukin (IL)-7 transgene under the control of E(alpha) promoter over-express IL-7 in MHC class II-positive cells and develop specific immune phenotype, marked by an increase in CD45R(+) cells in both the bone marrow and peripheral blood. We show that IL-7 transgenic mice have a bone phenotype characterized by an age-related loss of trabecular bone in both axial and long bones. Osteopenia was the result of increased number of active osteoclasts on the surface of trabecular bone. Furthermore, IL-7 transgenic mice showed increased osteoclastic but unchanged osteoblastic potential of the bone marrow in vitro. IL-7 over-expression also created osteoclastogenic microenvironment within the bone marrow which promoted the commitment of precursors towards the osteoclast lineage. These findings are important for immunological disturbances where IL-7 is involved and where alterations in the immune system are accompanied by changes in bone metabolism, such as multiple myeloma, rheumatoid arthritis and postmenopausal osteoporosis.
18954258 Tumor necrosis factor blockers influence macrophage responses to Mycobacterium tuberculosi 2008 Dec 15 Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine that mediates inflammation in response to various pathogens, including Mycobacterium tuberculosis, but is also a key factor in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. Three TNF-alpha-suppressing drugs have been approved to treat selected autoimmune diseases; 2 are monoclonal antibodies against TNF-alpha (adalimumab and infliximab), and the other is a soluble TNF receptor/Fc fusion protein (etanercept). TNF blockers have been shown to increase the risk of reactivation of latent tuberculosis, and this risk is higher in patients treated with the monoclonal antibodies. We studied the effects of TNF-alpha blockers on the maturation of mycobacteria-containing phagosomes in human macrophages. All 3 drugs had an inhibitory effect on IFN-gamma-induced phagosome maturation in phorbolmyristate acetate-differentiated human THP-1 cells. Adalimumab and infliximab, but not etanercept, suppressed phagosome maturation in primary human peripheral blood monocyte-derived macrophages in the presence or absence of IFN-gamma. Treatment of macrophages with TNF-alpha led to increased maturation of phagosomes containing Mycobacterium bovis bacillus Calmette-Guérin or M. tuberculosis H37Rv. These results suggest a role for TNF-alpha in activating phagosome maturation and highlight a mechanism through which TNF-alpha blockade can affect the host response to mycobacteria.
18923650 Long-range enhancer associated with chromatin looping allows AP-1 regulation of the peptid 2008 Transcription control at a distance is a critical mechanism, particularly for contiguous genes. The peptidylarginine deiminases (PADs) catalyse the conversion of protein-bound arginine into citrulline (deimination), a critical reaction in the pathophysiology of multiple sclerosis, Alzheimer's disease and rheumatoid arthritis, and in the metabolism of the major epidermal barrier protein filaggrin, a strong predisposing factor for atopic dermatitis. PADs are encoded by 5 clustered PADI genes (1p35-6). Unclear are the mechanisms controlling the expression of the gene PADI3 encoding the PAD3 isoform, a strong candidate for the deimination of filaggrin in the terminally differentiating epidermal keratinocyte. We describe the first PAD Intergenic Enhancer (PIE), an evolutionary conserved non coding segment located 86-kb from the PADI3 promoter. PIE is a strong enhancer of the PADI3 promoter in Ca2+-differentiated epidermal keratinocytes, and requires bound AP-1 factors, namely c-Jun and c-Fos. As compared to proliferative keratinocytes, calcium stimulation specifically associates with increased local DNase I hypersensitivity around PIE, and increased physical proximity of PIE and PADI3 as assessed by Chromosome Conformation Capture. The specific AP-1 inhibitor nordihydroguaiaretic acid suppresses the calcium-induced increase of PADI3 mRNA levels in keratinocytes. Our findings pave the way to the exploration of deimination control during tumorigenesis and wound healing, two conditions for which AP-1 factors are critical, and disclose that long-range transcription control has a role in the regulation of the gene PADI3. Since invalidation of distant regulators causes a variety of human diseases, PIE results to be a plausible candidate in association studies on deimination-related disorders or atopic disease.
18761068 A review of the taxonomy, ethnobotany, chemistry and pharmacology of Sutherlandia frutesce 2008 Oct 28 Sutherlandia frutescens (tribe Galegeae, Fabaceae), a popular plant in traditional medicine, is indigenous to South Africa, Lesotho, southern Namibia and southeastern Botswana. It is chemically, genetically and geographically extremely variable and has been divided into three subspecies and several regional forms. A second species, Sutherlandia tomentosa, is localized along the Cape coast. Sutherlandia is sometimes treated as part of the genus Lessertia. There are numerous vernacular names and a wide diversity of uses, including poor appetite, indigestion, stomach complaints, dysentery, colds, influenza, kidney conditions, fever, diabetes, internal cancers, uterine troubles, liver conditions, backache, rheumatoid arthritis, urinary tract infections, stress and anxiety, dropsy and heart failure. Notable is the use as a bitter tonic ("blood purifier"), anti-stress medication ('musa-pelo) and, at least since 1895, specifically as a cancer tonic (both as treatment and as prophylaxis). Externally it is applied to haemorrhoids, inflamed wounds and eye infections. Recent in vitro and in vivo studies have shown antiproliferative, anti-HIV, anti-diabetic, anti-inflammatory, analgesic, antibacterial, anti-stress, anticonvulsant and antithrombotic activities. Aqueous extracts often differ in activity from organic solvent extracts. The presence of high levels of free amino acids, non-protein amino acids such as canavanine and GABA, the cyclitol pinitol, flavonols and triterpenes (including SU1, a cycloartane-type triterpene saponin) provide plausible hypotheses on how these compounds, individually or collectively, may be responsible for the reputed efficacy in a wide range of ailments. Results of animal studies, as well as a phase I clinical study, have shown no indications of toxicity. Sufficient preclinical data are now available to justify controlled clinical studies.
18751917 The role of phospholipid oxidation products in inflammatory and autoimmune diseases: evide 2008 Since the discovery of oxidized phospholipids (OxPL) and their implication as modulators of inflammation in cardiovascular disease, roles for these lipid oxidation products have been suggested in many other disease settings. Lipid oxidation products accumulate in inflamed and oxidatively damaged tissue, where they are derived from oxidative modification of lipoproteins, but also from membranes of cells undergoing apoptosis. Thus, increased oxidative stress as well as decreased clearance of apoptotic cells has been implied to contribute to accumulation of OxPL in chronically inflamed tissues.A central role for OxPL in disease states associated with dyslipedemia, including atherosclerosis, diabetes and its complications, metabolic syndrome, and renal insufficiency, as well as general prothrombotic states, has been proposed. In addition, in organs which are constantly exposed to oxidative stress, including lung, skin, and eyes, increased levels of OxPL are suggested to contribute to inflammatory conditions. Moreover, accumulation of OxPL causes general immunmodulation and may lead to autoimmune diseases. Evidence is accumulating that OxPL play a role in lupus erythematosus, antiphospholipid syndrome, and rheumatoid arthritis. Last but not least, a role for OxPL in neurological disorders including multiple sclerosis (MS), Alzheimer's and Parkinson's disease has been suggested.This chapter will summarize recent findings obtained in animal models and from studies in humans that indicate that formation of OxPL represents a general mechanism that may play a major role in chronic inflammatory and autoimmune diseases.
18722015 In vitro affinity maturation of human GM-CSF antibodies by targeted CDR-diversification. 2008 Nov The mammalian immune system applies somatic hypermutation to select for antibodies with improved dissociation rates in vivo up to an intrinsic limit, previously termed as affinity ceiling. However, for certain therapeutic applications it may be desirable to further improve antibody affinities beyond that limit. In this study the selection of antibodies specific for the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) from the HuCAL GOLD human antibody library is described. In order to increase affinity and also functional activity, in vitro affinity maturation of a pool of lead Fab candidates was carried out. CDR-L3 and parallel CDR-H2 diversification using trinucleotide consensus cassettes were followed by the combination of optimized CDR-L3 and CDR-H2 leading to a 5000-fold improved affinity finally reaching a K(D) of 400 fM. Cytokine neutralizing potential of MOR04357 was evaluated in a TF-1 proliferation assay. Along with affinity optimization a 2000-fold increase in potency was observed compared to the parental antibody. Due to species cross-reactivity MOR04357 also blocks rat GM-CSF induced proliferation of FDCP-1 cells. Receptor inhibition studies showed that MOR04357 prevents the interaction of GM-CSF with the GM-CSF receptor alpha chain. As a consequence this leads to a blockade in signal transduction as measured by abolished STAT5 phosphorylation in the presence of GM-CSF and antibody. Due to its pro-inflammatory role GM-CSF has been implicated in the pathophysiology of inflammatory diseases like rheumatoid arthritis or asthma. Based on the mode of action described herein MOR04357 shows favourable antibody features as a potential drug candidate.
18650128 G/T polymorphism in the interleukin-2 exon 1 region among Han Chinese systemic lupus eryth 2008 Oct Interleukin-2 (IL-2), one of the crucial immunoregulatory cytokines required for T lymphocyte activation, plays an important role in autoimmune diseases. An IL-2 genetic G/T polymorphism (rs2069763) has been linked with multiple sclerosis and rheumatoid arthritis. We tested a hypothesis that this polymorphism confers systemic lupus erythematosus (SLE) susceptibility. Study participants were Han Chinese SLE patients and a healthy control group in Taiwan. Our results indicate (a) a significantly higher G allele frequency in SLE patients (P=1.91 x 10(-14); OR=3.94; 95% CI=2.74-5.66), (b) a significantly higher G allele frequency in SLE patients with antinuclear antibodies (ANA) (P=0.033; OR=4.21; 95% CI=1.01-17.51) and (c) a significantly lower G allele frequency in SLE patients with discoid rash (P=0.019; OR=0.41; 95% CI=0.19-0.88). Our results suggest that this polymorphism may be involved in the genetic background of Taiwanese SLE.
18564343 Increased proportion of CD56bright natural killer cells in active and inactive systemic lu 2009 Jan Natural killer (NK) cells belong to the innate immune system but can also affect adaptive immune reactions. This immune regulatory function is often ascribed to the CD56(bright) subpopulation of NK cells that is prevalent in secondary lymphoid tissues and has potent cytokine-producing ability. The NK cells have been described as affecting autoimmune disease and stimulating B-cell production of antibodies, but their role in systemic lupus erythematosus (SLE) pathology has not been extensively studied. We have studied NK cells in SLE, a B-cell-driven systemic autoimmune disease, and phenotypically characterized peripheral blood NK cells in comparison to NK cells from patients with immunoglobulin A nephritis, rheumatoid arthritis and healthy individuals. We have found an increased proportion of CD56(bright) NK cells in SLE, regardless of disease activity. We detected a somewhat increased expression of the activating receptor NKp46/CD335 on NK cells from SLE patients, although neither the percentage of NK cells of all lymphocytes nor the expression of other NK receptors analysed (LIR-1/CD85j, CD94, NKG2C/CD159c, NKG2D/CD314, NKp30/CD337, NKp44/CD336, CD69) differed between patient groups. We show that type I interferon, a proinflammatory cytokine known to be abundant in SLE, can cause increases of CD56(bright) NK cells in vitro. We confirmed that serum levels of interferon-alpha were increased in active, but not in inactive, disease in the SLE patient group. In conclusion, we found an increased proportion of CD56(bright) NK cells in the blood of SLE patients, although it remains to be examined whether and how this relates to the disease process.
18534087 Minocycline treatment results in reduced oral steroid requirements in adult asthma. 2008 May The tetracycline antibiotics have pleiotropic anti-inflammatory properties that may explain their therapeutic benefit in rheumatoid arthritis and acne. As these agents suppress both cellular and humoral immune responses, they may be of benefit in treating asthma and other allergic disorders. The purpose of this study was to determine whether minocycline therapy of asthma has steroid sparing effects beyond its inherent antibiotic properties. Adult asthmatic patients (n = 17) were treated with minocycline 150 mg p.o. twice daily or placebo for 8 weeks in a randomized, double-blind, placebo-controlled crossover study. Patients were evaluated for clinical improvement in oral steroid requirements, spirometry, and symptom scores (Asthma Quality of Life Questionnaire). They underwent assessment for preexisting infection (CT facial sinuses, Chlamydia pneumoniae nasopharyngeal culture, and C. pneumoniae and Mycoplasma pneumoniae serology). Minocycline use was associated with a 30% reduction in mean daily prednisone use compared with placebo (8.8 mg versus 14.4 mg, respectively; p = 0.02). Pulmonary function testing showed improvement in forced vital capacity (FVC; percent predicted; p = 0.03) and improvement in actual FVC and forced expiratory volume in 1 second (percent predicted) approached statistical significance (p = 0.05 and 0.08, respectively). Minocycline treatment was associated with significant improvement in asthma symptoms brought on by environmental triggers (p = 0.01). This preliminary study of minocycline therapy showed oral steroid-sparing properties for those with moderate persistent and severe persistent asthma.
18506734 Toxicity of radiotherapy in patients with collagen vascular disease. 2008 Aug 1 BACKGROUND: A diagnosis of collagen vascular disease (CVD) may predispose to radiotherapy (RT) toxicity. The objective of the current study was to identify factors that influence RT toxicity in the setting of CVD. METHODS: A total of 86 RT courses for 73 patients with CVD were delivered between 1985 and 2005. CVD subtypes include rheumatoid arthritis (RA; 33 patients), systemic lupus erythematosus (SLE; 13 patients), scleroderma (9 patients), dermatomyositis/polymyositis (5 patients), ankylosing spondylitis (4 patients), polymyalgia rheumatica/temporal arteritis (4 patients), Wegener granulomatosis (3 patients), and mixed connective tissue disorders (MCTD)/other (2 patients). Each patient with CVD was matched to 1 to 3 controls with respect to sex, race, site irradiated, RT dose (+/-2 Gray), and age (+/-5 years). RESULTS: There was no significant difference between CVD patients (65.1%) and controls (72.5%) experiencing any acute toxicity. CVD patients had a higher incidence of any late toxicity (29.1% vs 14%; P = .001), and a trend toward an increased rate of severe late toxicity (9.3% vs 3.7%; P = .079). RT delivered to the breast had increased risk of severe acute toxicity, whereas RT to the pelvis had increased risk of severe acute and late toxicity. RT administered in the setting of scleroderma carried a higher risk of severe late toxicity, whereas RT to SLE patients carried a higher risk of severe acute and late toxicity. CONCLUSIONS: Although generally well tolerated, RT in the setting of CVD appears to carry a higher risk of late toxicity. RT to the pelvis or in the setting of SLE or scleroderma may predispose to an even greater risk of severe toxicity. These issues should be considered when deciding whether to offer RT for these patients.
18452068 Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia. 2008 May T cell large granular lymphocyte leukemia (T-LGL) is characterised by semiautonomous proliferation of monoclonal cytotoxic T lymphocytes, which can result in neutropenia, splenomegaly, and is associated with various autoimmune disorders, particularly rheumatoid arthritis. The coexistence of T-LGL leukemia with B cell abnormalities has previously been identified in case reports. However, no systematic analysis to determine the frequency of this co-association has been reported. Analysis of 63 T-LGL patients revealed a frequent association with humoral immune system abnormalities. We identified coexisting B cell dyscrasias in 17 T-LGL patients (27% of total), of whom 12 had monoclonal gammopathy of unknown significance (MGUS) (19%), and 5 had chronic lymphocytic leukemia (CLL) (8%). The presence of both MGUS and CLL was found in 2 patients (3%) and follicular lymphoma was identified with MGUS in another T-LGL patient (2%). Additionally, polyclonal hypergammaglobulinemia or hypogammaglobulinemia was found in 10 additional LGL leukemia patients bringing the total frequency of B cell abnormalities in T-LGL leukemia to 43% in our cohort. The co-association of B cell pathology with T-LGL suggests that either a common antigen drives clonal B and T cells, or that humoral malignancy could serve as the stimulus for lymphocyte expansion representing an overactive anti-tumour surveillance.
18375774 Restless legs syndrome in type 2 diabetes: implications to diabetes educators. 2008 Mar PURPOSE: The purpose of this study was to provide a background of restless legs syndrome (RLS), present the prevalence and demographic findings of a descriptive study of type 2 diabetes with RLS, and provide implications to diabetes educators on the management and education of RLS. METHODS: Participants with type 2 diabetes who met the diagnostic criteria for RLS based on the International RLS Study Group Criteria were recruited from the PENN Rodebaugh Diabetes Center from July 2005 through September 2006. Participants who met inclusion and exclusion criteria were mailed a survey to collect data. RESULTS: Of 121 patients with type 2 diabetes, 54 (45%) of the screened sample met the 4 diagnostic criteria for RLS. Of those who met the inclusion and exclusion criteria of the primary study, 18 patients with type 2 diabetes with RLS participated in this study. Along with diabetes, the participants had a variety of comorbid health conditions including hypertension, neuropathies, rheumatoid arthritis, renal failure, and irritable bowel syndrome. Only one third of the participants were being treated for RLS. Thirty-nine percent of the participants with type 2 diabetes were using insulin to manage their diabetes with other oral agents. CONCLUSIONS: RLS is a sleep disorder that may affect the management of type 2 diabetes. Diabetes educators must know that sleep disorders can affect long-term health outcomes, and RLS is frequently seen in this cohort of patients.
18300798 IgG4-positive plasma cells in inflammatory abdominal aortic aneurysm: the possibility of a 2008 Apr Inflammatory abdominal aortic aneurysm (IAA) is associated with autoimmune disease. However, the precise mechanism of IAA remains unclear. There is increasing evidence that IgG4 is involved in the autoimmune mechanism of various idiopathic sclerosing lesions, including sclerosing pancreatitis and retroperitoneal fibrosis. The present study investigated the hypothesis that the IgG4-related autoimmune reaction is involved in the formation of IAA. The study group consisted of 11 cases of IAA (69.2 +/- 8.59y) and 12 age-matched cases of atherosclerotic abdominal aortic aneurysm (AAA, 69.6 +/- 5.94y), which were used in the previous report. A clinicopathologic examination of these lesions was performed, including histology and immunohistochemistry, in relation to the involvement of IgG4-positive plasma cells in the formation of IAA. No difference in the incidence of risk factors for atherosclerosis was observed between the patients with IAA and AAA. Autoimmune diseases were diagnosed in 2 patients with IAA, including rheumatoid arthritis and polyarteritis nodosa. A patient with IAA had pulmonary fibrosis. In contrast, autoimmune diseases were absent in patients with AAA. However, there was no significant difference in the incidence of autoimmune diseases between the patients with IAA and AAA. Lymphocyte and plasma cell infiltration and fibrosis were significantly more intense and extensive in IAA than in AAA. In addition, lymph follicle formation and vasculitis of small veins and arteries were frequently found in the affected lesions of IAA. Immunohistochemically, IAA showed a significant increase in the number of infiltrating IgG4-positive plasma cells and the incidence of a disrupted follicular dendritic cell network in lymph follicles, in comparison with AAA. These findings suggest that IAA may be an aortic lesion reflecting the presence of IgG4-related sclerosing disease, and not a simple inflammatory aneurysm of the aorta.
18264787 Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycat 2008 Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFkappaB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFkappaB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.
17704062 The development of a preliminary ultrasonographic scoring system for features of hand oste 2008 May OBJECTIVES: Painful osteoarthritis (OA) of the hand is common and a validated ultrasound (US) scoring system would be valuable for epidemiological and therapeutic outcome studies. US is increasingly used to assess peripheral joints, though most of the US focus in rheumatic diseases has been on rheumatoid arthritis. We aimed to develop a preliminary US hand OA scoring system, initially focusing on relevant pathological features with potentially high reliability. METHODS: A group of experts in the fields of OA, US and novel tool development agreed on domains and suggested scaling of the items to be used in US hand OA scoring systems. A multi-observer reliability exercise was then performed to evaluate the draft items. RESULTS: Synovitis (grey scale and Power Doppler) and osteophytes (representing activity and damage domains) were included and evaluated as the initial components of the scoring system. All three features were evaluated for their presence/absence and if present were scored using a 1-3 scale. The reliability exercise demonstrated intra-reader kappa values of 0.444-1.0, 0.211-1.0 and 0.087-1.0 for grey scale synovitis, power Doppler and osteophytes respectively. Inter-reader reliability kappa values were 0.398, 0.327 and 0.530 grey-scale synovitis, power Doppler and osteophytes respectively. Without extensive standardisation, both intra- and inter-reader reliability were moderately good. CONCLUSIONS: The draft scoring system demonstrated substantive to almost perfect percentage exact agreement on the presence/absence of the selected OA features and moderate to substantive percentage exact agreement on semi-quantitative grading. This preliminary process provides a good basis from which to further develop an US outcome tool for hand OA that has the potential to be utilised in multicentre clinical trials.
17654172 Preparation and evaluation of biodegradable flubiprofen gelatin micro-spheres for intra-ar 2007 Sep PURPOSE: A controlled release delivery system that localizes flurbiprofen (FP) in synovial joint is prefered to treat inflammation in rheumatoid arthritis (RA). The purpose of this study is to develop and characterize FP-loaded gelatin microspheres and evaluate FP plasma concentrations following intra-articular injection into healthy rabbits. METHODS: Flurbiprofen gelatin microspheres (FP-GMS) were prepared by a emulsion-congealing method. The RP-HPLC method was established to determine the FP concentraion in plasma. The particle size of FP-GMS with optimized formulation was 2.5 approximately 12.3 microm with a mean size of gelatin microspheres of 7.53 microm. The drug loading efficiency was 5.02% (w/w). The dissolution profile of the FP-GMS was depicted by Higuchi kinetics. RESULTS: The half time for 50% release of FP from FP-GMS (t(50)) was 5.58 h. A total of 96% original FP was remained in the microspheres after being stored under 75% humidity and 37 degrees C for 3 months. The pharmacokinetics study demonstrated that the mean resident time (MRT) of FP in the FP-GMS group was prolonged vs. the injection group significantly (p < 0.01) after intra-articular administration into healthy rabbit hind joints. The T(p) of FP-GMS group was prolonged by 2.03-times and the C(max) was decreased by 5.57-times vs. that of the injection group, respectively. The FP plasma concentration in FP-GMS was 8-fold higher than that of the FP injection group at 8 h. In addition, FP was rapidly cleared from blood circulation within 8 h with the injection group while FP was retained for more than 24 h with the FP-GMS group. CONCLUSIONS: These data indicate that the simple emulsion-congealing method can be used to encapsulate water soluble drugs such as FP for the treatment of inflammatory disease within the joint cavity.
17526805 Phosphoinositide 3-kinase gamma inhibition plays a crucial role in early steps of inflamma 2007 Sep Leukocyte trafficking to inflammatory sites is a gradual process, which is dominated in its early phases by chemokine- and cytokine-mediated neutrophil recruitment. The chemokine regulated on activation normal T cell expressed and secreted (RANTES) has been shown to be highly expressed in the joints of patient with rheumatoid arthritis and to promote leukocyte trafficking into the synovial tissue. In this study, we investigated the effect of RANTES in a murine model of peritoneal chemotaxis, and we found that RANTES dose-dependently induces neutrophil recruitment. Then, through morphological and histological analyses, we observed that activated neutrophils represent the major infiltrating population in response to RANTES chemotactic stimulus. Furthermore, we demonstrated that oral administration of either nonisoform-specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (morpholin-4-yl-8-phenylchromen-4-one) or selective PI3Kgamma inhibitor AS041164 (5-benzo[1,3]dioxol-5-ylmethylene-thiazolidine-2,4-dione) blocks RANTES-induced chemotaxis and reduces the level of AKT phosphorylation. Because the two compounds showed a similar pharmacokinetic profile in terms of bioavailability and half-life after oral route administration, the selective inhibition of the PI3Kgamma-isoform pathway through AS041164 was three times more potent in reducing neutrophil recruitment. Finally, to confirm the blockade of neutrophil infiltration that occurs in the early phase of the inflammatory response, AS041164 was also tested in a model of carrageenan-induced paw edema in rats. Therefore, the PI3Kgamma pathway plays an important role in controlling neutrophil chemotaxis during early steps of inflammation.