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ID PMID Title PublicationDate abstract
16796622 Quinine sulfate inhibits invasion of some bacterial skin pathogens. 2006 Jun BACKGROUND: As some of the many patients who receive antimalarials for the treatment of noninfective inflammatory diseases (lupus erythematosus, collagen vascular diseases, rheumatoid arthritis, and others) are also immunosuppressed because of their disease and/or treatments, and may have concomitant bacterial infections, we investigated the effect of these drugs on the growth and invasion of several bacteria that are commonly associated with skin and soft tissue infections to determine whether they could protect against such conditions and obviate the need for an additional antibiotic drug. METHODS: The effect of quinine sulfate (QS) at concentrations of 50 and 100 microm on the entry process of Enterobacter agglomerans, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae into Caco-2 cells was studied during the infection period. The invasive efficiency was expressed as the number of viable internalized bacteria obtained by counting the colony-forming units (CFUs). RESULTS: The invasive ability of E. agglomerans and S. aureus was significantly inhibited by 50 and 100 microm QS in a dose-dependent manner when the drug was added to Caco-2 cell monolayers during the infection period; however, QS had no significant effect on the internalization of P. aeruginosa or K. pneumoniae. DISCUSSION AND CONCLUSIONS: Antimalarial drugs are currently widely used to treat patients with autoimmune dermatologic and rheumatologic diseases, and have also been recently proposed as additional therapy for patients with human immunodeficiency virus (HIV) infection. These patients, who are often immunocompromised, may receive a secondary advantage from these antimalarials, which may provide some protection against staphylococci (amongst the most important human pathogens causing many superficial and systemic infections) and E. agglomerans.
16741469 An analysis of the risk of hip dislocation with a contemporary total joint registry. 2006 Jun Dislocation rates after total hip arthroplasty in a community setting have not been well documented. We used a community based joint registry to evaluate hip dislocations that occurred within 1 year after total hip arthroplasty. We evaluated patient, implant, and technical factors associated with dislocation, including primary versus revision surgery, femoral head size (28 mm versus > or = 32 mm), operative time, surgeon volume, surgical approach, age, gender, diagnosis, American Society of Anesthesiologists (ASA) classification, and body mass index (BMI). There were 1693 primary total hip arthroplasties and 277 revision procedures performed from 2001-2003. The overall dislocation rate was 1.7% for primary total hip arthroplasties and 5.1% for revision procedures. Patients with ASA scores of 3 or 4 had a 2.3-fold dislocation increase compared with patients with scores of 1 or 2. Patients with rheumatoid arthritis had an increased risk of dislocation. The dislocation rates for primary total hip arthroplasty were 2% for 28 mm heads and 0.7% for heads > or = 32 mm. The surgeon's patient volume, surgical approach, operative time, and body mass index had no effect on dislocation.
16529763 Improved solubilization of Celecoxib in U-type nonionic microemulsions and their structura 2006 Jul 1 Celecoxib (clxb) is an important drug for treatment of rheumatoid arthritis and osteoarthritis by specifically inhibiting the enzyme cyclooxygenase-2 (COX-2). Clxb is a type 2 drug characterized by low water solubility (<5 mug/ml) and fast transmembrane transport. The present formulations require high dosage since the transmembrane transport fluctuates and is very difficult to control. Dissolving the drug within an oil phase was not practical since its dissolution was very small and its dispersion in water was impossible. In our recent studies, we learned to construct U-type phase diagrams and to formulate reverse microemulsions (oil-based concentrates) that are progressively and fully dilutable with aqueous phase. In the present study, we solubilized clxb in nanostructures of reverse micelles of U-type nonionic microemulsions that consisted of R(+)-limonene, alcohol, propylene glycol (PG), and hydrophilic surfactant (Tween 60). The solubilization capacity of the drug in these systems is many times higher than in either the oil or the aqueous phase. The clxb solubilized microemulsions are fully diluted with aqueous phase without phase separation. The solubilization capacity decreases as the water content increases. Electrical conductivity, viscosity, and self-diffusion (SD) coefficients of the microemulsion components were measured along a suitable water dilution line. The three major microemulsion regions were detected and the transitions between the W/O to bicontinuous phase and from this phase to the O/W droplets were identified (at 30 and 70 wt% aqueous phase, respectively). From the SD coefficients, it was found that the drug is initially solubilized at the interface of the W/O droplets and there are no significant structural changes. The transition to a bicontinuous phase occurs at the same water content as in the empty (i.e., without drug) system. From the viscosity profiles, we concluded that the drug affects the structure of the bicontinuous phase as reflected in the water content at which the oil-continuous network is destroyed and full inversion occurs (50 vs 55 wt% in the drug-loaded system). Upon further dilution the drug remains solubilized at the interface and is oriented with its hydrophilic part facing the water, and is strongly affects the inversion to O/W droplets. From Small Angle X-ray Scattering (SAXS) measurements we learned that the drug effects the structure of microemulsion droplets and forms "ill-defined structures," probably less spherical. Yet, the overall droplet sizes at the high dilutions did not change very much.
18289383 Human articular chondrocytes produce IL-7 and respond to IL-7 with increased production of 2008 INTRODUCTION: Fibronectin fragments have been found in the articular cartilage and synovial fluid of patients with osteoarthritis and rheumatoid arthritis. These matrix fragments can stimulate production of multiple mediators of matrix destruction, including various cytokines and metalloproteinases. The purpose of this study was to discover novel mediators of cartilage destruction using fibronectin fragments as a stimulus. METHODS: Human articular cartilage was obtained from tissue donors and from osteoarthritic cartilage removed at the time of knee replacement surgery. Enzymatically isolated chondrocytes in serum-free cultures were stimulated overnight with the 110 kDa alpha5beta1 integrin-binding fibronectin fragment or with IL-1, IL-6, or IL-7. Cytokines and matrix metalloproteinases released into the media were detected using antibody arrays and quantified by ELISA. IL-7 receptor expression was evaluated by flow cytometry, immunocytochemical staining, and PCR. RESULTS: IL-7 was found to be produced by chondrocytes treated with fibronectin fragments. Compared with cells isolated from normal young adult human articular cartilage, increased IL-7 production was noted in cells isolated from older adult tissue donors and from osteoarthritic cartilage. Chondrocyte IL-7 production was also stimulated by combined treatment with the catabolic cytokines IL-1 and IL-6. Chondrocytes were found to express IL-7 receptors and to respond to IL-7 stimulation with increased production of matrix metalloproteinase-13 and with proteoglycan release from cartilage explants. CONCLUSION: These novel findings indicate that IL-7 may contribute to cartilage destruction in joint diseases, including osteoarthritis.
18031725 Effect of prostanoid EP4 receptor antagonist, CJ-042,794, in rat models of pain and inflam 2008 Feb 2 Recent study suggests that the proinflammatory and nociceptive effects of prostaglandin E(2) are mediated by prostanoid receptor subtype EP(4) and prostanoid EP(4) receptor may be a potential target for the treatment of inflammatory pain. Here we describe pharmacological characterization of a novel prostanoid EP(4) receptor antagonist, CJ-042,794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl) oxy] phenyl} carbonyl) amino] ethyl} benzoic acid) in comparison with piroxicam (non-steroidal anti-inflammatory drug) or rofecoxib (cyclooxygenase-2 inhibitor). CJ-042,794 competitively antagonized cAMP accumulation with a pA(2) value of 8.7 in HEK293 cells overexpressing rat prostanoid EP(4) receptors. Orally administered CJ-042,794 dose-dependently inhibited carrageenan-induced mechanical hyperalgesia with an ED(50) value of 4.7 mg/kg (11 micromol/kg) and its maximal activity was somewhat less effective than that of 10 mg/kg piroxicam (30 micromol/kg p.o.). When CJ-042,794 and rofecoxib were administered to adjuvant-induced arthritis rats on Days 12-22 twice daily, both compounds reversed paw swelling to normal levels. These results suggest that a pharmacological blockade of the prostanoid EP(4) receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.
21289940 Benefits and risks of hormonal contraception for women. 2007 Aug 10 SCIENTIFIC BACKGROUND: A large proportion of women of reproductive age in Germany use various methods of pregnancy prevention (contraception), among them various hormone-based methods. Hormonal contraceptives may be divided into combined estrogen-progestogen contraceptives (pills, skin patches, vaginal rings), progestogen-only contraceptives (pills, injections, implants, hormone spirals) and emergency contraceptives. RESEARCH QUESTIONS: The evaluation addressed the question of benefits and risks of hormonal contraceptives, their economic effects as well as their ethical-social and legal implications. METHODS: A systematic literature search was conducted in April 2006 starting from 2000. The evaluation is primarily based on systematic reviews. RESULTS: In perfect use, all hormonal contraceptives excluding emergency contraceptives proved to be the most effective reversible contraceptive methods (rate of unintended pregnancies 0.05% to 0.3%). However, the typical use of oral contraceptives, injections, skin patches, and vaginal rings, which also considers possible application errors, showed a lower contraceptive efficacy (rate of unintended pregnancies 3% to 8%). It was lower than that of copper spirals. The risk of venous thromboembolism increased three to six times in users of hormonal contraceptives, the risks of stroke and myocardial infarction two to three times. The risk declined after discontinuation of use. The effects were estrogen-dose and progestogen-type dependent. The use of hormonal contraceptives showed a relative risk of ovarian and endometrial carcinomas of approximately 0.5 or 0.7, of breast and cervical cancer of approximately 1.2 or 1.6. The effect remained several years after discontinuation of use. The results concerning hepatocellular carcinoma suggested a carcinogenic effect. In women with acne, an improvement due to use of hormonal contraceptives was proven. Cervical chlamydial infections were more frequent in users of hormonal contraception. Headache appeared mostly only at the beginning of the use of combined oral contraceptives. Progestogen-only contraceptives worsened the results of the glucose tolerance test. A review of low evidence reported further risks of hormonal contraceptives (concerning menstrual problems, ovarian cysts, bone density, thyroid diseases and rheumatoid arthritis) as well as further benefits (concerning blood pressure and Crohn's disease). Hormonal spirals were shown to be more effective than spirals which do not release hormones. In emergency contraception, Levonorgestrel was more effective than the Yuzpe method. Most other proven differences between hormonal contraceptives were related to menstrual problems. After spirals with or without hormone release, the other hormonal contraceptives were shown in typical use to be the second most cost-effective reversible methods of contraception. DISCUSSION: The addressed questions could be answered only on relatively low evidence level, partly only for applications with estrogen doses which are not used in Germany any more. The transferability of the results of the analysed primary health-economics studies on the current situation in Germany is limited (clinical assumptions from out-dated information sources of low evidence levels, cost assumptions from the American health system). CONCLUSIONS: In perfect use, hormonal contraceptives have to be classified as the most effective reversible contraceptive methods. For the individual decision concerning the use of hormonal contraception, benefits should be related to the additional risks. Alternative methods such as spirals should be prioritised if perfect use seems to be impossible. In this case, spirals are also preferable from health-economics perspective. No ethical-social or legal conclusions can be derived from the available data.
17062137 Alpha-actinin-binding antibodies in relation to systemic lupus erythematosus and lupus nep 2006 This study investigated the overall clinical impact of anti-alpha-actinin antibodies in patients with pre-selected autoimmune diseases and in a random group of anti-nuclear antibody (ANA)-positive individuals. The relation of anti-alpha-actinin antibodies with lupus nephritis and anti-double-stranded DNA (anti-dsDNA) antibodies represented a particular focus for the study. Using a cross-sectional design, the presence of antibodies to alpha-actinin was studied in selected groups, classified according to the relevant American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE) (n = 99), rheumatoid arthritis (RA) (n = 68), Wegener's granulomatosis (WG) (n = 85), and fibromyalgia (FM) (n = 29), and in a random group of ANA-positive individuals (n = 142). Renal disease was defined as (increased) proteinuria with haematuria or presence of cellular casts. Sera from SLE, RA, and Sjøgren's syndrome (SS) patients had significantly higher levels of anti-alpha-actinin antibodies than the other patient groups. Using the geometric mean (+/- 2 standard deviations) in FM patients as the upper cutoff, 20% of SLE patients, 12% of RA patients, 4% of SS patients, and none of the WG patients were positive for anti-alpha-actinin antibodies. Within the SLE cohort, anti-alpha-actinin antibody levels were higher in patients with renal flares (p = 0.02) and correlated independently with anti-dsDNA antibody levels by enzyme-linked immunosorbent assay (p < 0.007) but not with other disease features. In the random ANA group, 14 individuals had anti-alpha-actinin antibodies. Of these, 36% had SLE, while 64% suffered from other, mostly autoimmune, disorders. Antibodies binding to alpha-actinin were detected in 20% of SLE patients but were not specific for SLE. They correlate with anti-dsDNA antibody levels, implying in vitro cross-reactivity of anti-dsDNA antibodies, which may explain the observed association with renal disease in SLE.
16787194 Cyclooxygenase-2 inhibitors: a painful lesson. 2006 Jun Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.
18507870 JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-ka 2008 May 29 BACKGROUND: Bee venom therapy has been used to treat inflammatory diseases including rheumatoid arthritis in humans and in experimental animals. We previously found that bee venom and melittin (a major component of bee venom) have anti-inflammatory effect by reacting with the sulfhydryl group of p50 of nuclear factor-kappa B (NF-kappaB) and IkappaB kinases (IKKs). Since mitogen activated protein (MAP) kinase family is implicated in the NF-kappaB activation and inflammatory reaction, we further investigated whether activation of MAP kinase may be also involved in the anti-inflammatory effect of melittin and bee venom. METHODS: The anti-inflammatory effects of melittin and bee venom were investigated in cultured Raw 264.7 cells, THP-1 human monocytic cells and Synoviocytes. The activation of NF-kappaB was investigated by electrophoretic mobility shift assay. Nitric oxide (NO) and prostaglandin E2 (PGE2) were determined either by Enzyme Linked Immuno Sorbent Assay or by biochemical assay. Expression of IkappaB, p50, p65, inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2) as well as phosphorylation of MAP kinase family was determined by Western blot. RESULTS: Melittin (0.5-5 mug/ml) and bee venom (5 and 10 mug/ml) inhibited lipopolysaccharide (LPS, 1 mug/ml) and sodium nitroprusside (SNP, 200 muM)-induced activation of c-Jun NH2-terminal kinase (JNK) in RAW 264.7 cells in a dose dependent manner. However, JNK inhibitor, anthra [1,9-cd]pyrazole-6 (2H)-one (SP600215, 10-50 muM) dose dependently suppressed the inhibitory effects of melittin and bee venom on NF-kappaB dependent luciferase and DNA binding activity via suppression of the inhibitory effect of melittin and bee venom on the LPS and SNP-induced translocation of p65 and p50 into nucleus as well as cytosolic release of IkappaB. Moreover, JNK inhibitor suppressed the inhibitory effects of melittin and bee venom on iNOS and COX-2 expression, and on NO and PGE2 generation. CONCLUSION: These data show that melittin and bee venom prevent LPS and SNP-induced NO and PGE2 production via JNK pathway dependent inactivation of NF-kappaB, and suggest that inactivation of JNK pathways may also contribute to the anti-inflammatory and anti-arthritis effects of melittin and bee venom.
17665452 Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection in mi 2007 Aug OBJECTIVE: Treatment of rheumatoid arthritis and other autoimmune disorders with anti-tumor necrosis factor (anti-TNF) agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis. While the mechanism of action of abatacept is fundamentally different from that of anti-TNF therapies, its effect on the protective response to latent tuberculosis is not known. We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection. METHODS: Chronic M tuberculosis infection was established in C57BL/6 mice. Four months after infection, mice were treated for up to 16 weeks with abatacept, anti-murine TNF antibody, or vehicle. The primary end point was survival; body weight, bacterial load, histologic features, interferon-gamma (IFNgamma) production by T cells, and cellular infiltration were also assessed. RESULTS: Abatacept- and vehicle-treated groups both maintained control of M tuberculosis infection, with 100% survival after 16 weeks of treatment. These 2 groups had no significant differences in body weight, no clinically relevant differences in bacterial load in the lungs, lymph nodes, or spleen, and no differences in the mean percentage of total or activated T cells, macrophages, neutrophils, or B cells, or in IFNgamma production in the lung or lymph nodes. In contrast, 100% mortality was seen in the anti-TNF antibody-treated group by week 9, with significant body weight loss and increased bacterial load in the lungs, lymph nodes, and spleen. Furthermore, the anti-TNF antibody-treated group had increased pathology consistent with the exacerbation of M tuberculosis infection. CONCLUSION: Abatacept did not impair the ability of mice to control a chronic M tuberculosis infection. In contrast, mice treated with anti-TNF therapy showed increased pathology and bacterial load, with 100% mortality by week 9. The clinical significance of these findings has not yet been determined.
17223874 A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis 2007 Feb BACKGROUND: Infliximab, an antitumour necrosis factor-alpha chimeric monoclonal antibody, is effective for the treatment of severe psoriasis. While the induction of antinuclear antibodies (ANA) and antidouble-stranded-DNA antibodies (anti-dsDNA-ab) is frequently observed in patients with rheumatoid arthritis and Crohn disease receiving infliximab, the incidence of induced biological and clinical autoimmunity remains unknown in the context of psoriasis. OBJECTIVES: To investigate biological and clinical signs of autoimmunity in 28 patients receiving infliximab for severe, recalcitrant forms of psoriasis, and the clinical response to treatment. METHODS: Twenty-eight patients, 15 men and 13 women (median age 39.4 years) with psoriasis refractory to three or more systemic treatments were included. Twenty presented with plaque-type psoriasis [median Psoriasis Area and Severity Index (PASI) score 25.9; range 7.2-48], five with psoriatic erythroderma (median PASI score 54; range 48-72) and three with generalized pustular psoriasis (GPP). Psoriatic arthritis was present in 13 patients (46.4%). Infliximab 5 mg kg(-1) was given at week (W) 0, W2, W6 and every 8 weeks thereafter. Clinical data were assessed at baseline and before each infusion. Detection of ANA and of IgM and IgG anti-dsDNA-ab were performed at baseline and at W22 by immunofluorescence and enzyme-linked immunosorbent assay, respectively. RESULTS: The mean number of infliximab infusions was 5.5 (range 2-15). Among patients with plaque-type and erythrodermic psoriasis, 17 of 25 (68%) and three of five reached a PASI improvement of 75% or more, respectively, while rapid improvement of clinical and biological signs was observed in all three patients with GPP. The prevalence of positive detection of ANA raised from 12% at baseline to 72% at W22 (P = 0.0001), an increase which was also observed for IgM anti-dsDNA-ab (68% vs. 0%, P < 0.0001), while no significant change was observed for the IgG isotype (16% vs. 0%, P = 0.125). Three patients developed nonerosive polyarthritis, without any other criteria for systemic lupus. CONCLUSIONS: The incidence of biological autoimmunity is high in patients with refractory psoriasis receiving infliximab. The concomitant onset of polyarthritis in three cases raises the need to investigate the incidence of autoimmune manifestations in psoriatic patients receiving infliximab in further large-scale studies.
19065799 Immune receptor signaling, aging and autoimmunity. 2008 Aging is associated with a myriad of changes including alterations in glucose metabolism, brain function, hormonal regulation, muscle homeostasis and the immune system. Aged dividuals, generally still defined as over 65 years old, differ from middle-aged or young donors in many features of the immune system. The major observation is that the elderly population is not able to cope with infections as well as younger adults and recovery generally takes longer. Moreover, some diseases first appear with advancing age and are likely associated with dysfunction of the immune system. Thus, Alzheimer's disease, atherosclerosis, type II diabetes and some autoimmune disorders are linked to changes in immune function. One major immune cell population implicated as being responsible for the initiation and chronicity of immune dysfunction leading to diseases or immunosuppression is the T-cell. Although many changes in B-cell and innate immune function in aging are associated with the appearance of disease, they are not as well studied and clearly demarcated as changes in the T-cell compartment. The adaptive immune system is coordinated by T-cells, the activation of which is required for the initiation, maintenance and termination of responses against pathogens. Changes in the expression and functions of the T-cell receptor (TCR) for antigen and its co-receptors are closely associated with immunosenescence. Certain similar changes have also been found in some other disease states, e.g., rheumatoid arthritis, systemic lupus erythematosus and cancer. In this chapter, we will summarize our knowledge about multichain immune recognition receptor signaling, mainly the TCR, in aging and autoimmune diseases.
19018002 Promiscuous interaction between gold-specific T cells and APCs in gold allergy. 2008 Dec 1 Gold compounds clinically used as immunomodulators have high potential to evoke hypersensitivity reactions as an adverse effect. To explore the mechanism of gold allergy, we immunologically characterized T cells infiltrating skin rashes and generated 44 gold-specific T cell clones and lines from a rheumatoid arthritis patient who developed skin rashes and systemic symptoms after gold treatment. CD4(+) and CD8(+) cells predominantly infiltrating the skin rashes and some of the T cell clones and lines shared common Vbetas. These cells exhibited Th0-like, Th2-like, and Tc1-like cytokine profiles, and showed chemotactic activities for thymus and activation-regulated chemokine and IFN-gamma-inducible protein-10 corresponding to the cytokine profiles. T cell recognition of gold consisted of MHC-restricted and MHC-independent pathways. Blocking studies with anti-MHC Abs indicated that the groove of MHC in APCs, where Ags should ordinarily be settled, did not serve as a conjugating site of gold for these T cells in certain cases. These observations raise the possibility that gold-specific CD4(+) and CD8(+) T cells and APCs promiscuously interact under stimulation with gold, resulting in various clinical manifestations in gold allergy.
19005742 Nanometer- and submicrometer-sized hollow spheres of chondroitin sulfate as a potential fo 2009 Feb PURPOSE: The synthesis of nanometer and submicrometer hollow particles could be a motivating way to imprint new therapeutic properties into a chondroitin sulfate-based hydrogel formulation. The use of hollowed polymer structures as a formulation strategy is expected to have an impact in the effective therapy in the treatment of rheumatoid arthritis. METHODS: Chemical modification of the chondroitin sulfate with glycidyl methacrylate (GMA) was performed in water under thermal and acid stimuli. The hydrogel spheres were formed upon cross-linking reaction of modified chondroitin sulfate (CSM) in a water-in-benzyl alcohol nano-droplet emulsion. RESULTS: 1H NMR and 13C NMR spectra showed that the carbon-carbon pi-bonds coming from the GMA were incorporated onto backbones of CS. 13C-CP/MAS NMR spectra revealed that the formation of the CSM hydrogel spheres during the dispersion stage occurred by way of carbon-carbon pi-bonds on the CSM structure. The spherical shapes of the particles with diameters in the range of 20 microm to 500 nm were very clearly verified by SEM images where the dark center and edge of the hollow spheres could be identified easily. CONCLUSIONS: Nanometer- and submicrometer-sized hydrogel spheres with hollow interior were produced from chondroitin sulfate by using a new strategy of hydrogel synthesis.
18855647 Inhibitors of vascular endothelial growth factor in cancer. 2008 Oct Angiogenesis is a complex process that is regulated by pro- and antiangiogenic factors. These factors can emanate from diverse sources including cancer cells, stromal cells, blood and extracellular matrix. Their relative contribution is likely to change with tumor type and tumor site. Vascular endothelial growth factor (VEGF) is now well confirmed as the primary and the most potent inducer of angiogenesis. To activate cellular signaling pathways, VEGF binds to receptor kinases VEGF-R1, R2 and R3. It then promotes several events required for the formation of new blood vessels, such as endothelial cell survival, proliferation, migration and vascular permeability. Activation of endothelial cells, leads to the secretion of enzymes which degrade the extracellular matrix (ECM) and hence promote metastasis. Similarly it promotes survival by inducing Bcl-2 expression on VEGF receptor positive leukemia. Besides being a potent mitogen for macrovascular cells derived from arteries, veins and lymphatics, it is also highly involved in a number of angiogenic related disorders including inflammatory diseases, rheumatoid arthritis, psoriasis, retinopathies and age related macular degeneration. Neovascularization and increased vessel permeability are being recognized as major causes of VEGF related pathogenesis. Therefore, inhibition of VEGF pathway is a strategy being widely pursued to provide new therapeutics for the treatment of VEGF related disorders. Over twenty compounds with anti-angiogenic properties ranging from VEGF neutralizing antibody, soluble receptors, receptor antagonists or tyrosine kinase inhibitors (TKIs) are either approved or are currently under clinical (phase I - III) study. This review aims to provide an updated account of how VEGF inhibitors are shaping up to become an important class of drugs used in the treatment of cancer.
18790041 Effects of bee venom on the maturation of murine dendritic cells stimulated by LPS. 2008 Nov 20 AIM OF STUDY: This study was performed to elicit the effectiveness of bee venom (BV), a traditional immunosuppressive Korean acupuncture agent, on the maturation of dendrtic cells (DCs). MATERIALS AND METHODS: Immature dendritic cells (iDCs) were generated from mouse bone marrow cells with GM-CSF. After 10 days of initial differentiation, DCs were activated with lipopolysaccharides (LPS) for another 48h in the presence or absence of BV. Surface molecule analysis, intracytoplasmic staining of cytokines, FITC-conjugated antigen uptake, and transwell migration assays were conducted with iDCs and activated DCs. RESULTS: Up-regulation of costimulatory molecules, typical of mature DCs (mDCs) was inhibited by addition of BV. Pro-inflammatory cytokines were also found to be reduced with BV treatment in LPS-stimulated DC. A decrease in antigen uptake upon the maturation of DC was reversed in low dose BV treated mDC. In addition, BV treated mDC demonstrated reduced directional migration in response to CCL21, a lymphoid chemokine which directs mDC. CONCLUSIONS: BV may have a therapeutic effect an on abnormally activated immune status, such as autoimmune rheumatoid arthritis, through an immune-modulatory effect on DC.
18688909 Musculoskeletal manifestations and rheumatic symptoms in patients with cystic fibrosis (CF 2008 Sep OBJECTIVE: To determine the character and frequency of musculoskeletal manifestations and rheumatic symptoms in patients with cystic fibrosis (CF). METHODS: Rheumatic symptoms and signs of 70 patients with CF (age 6 to 61 yrs) were determined by interview and clinical assessment. Age and sex-matched healthy volunteers served as a control group. In CF patients, laboratory measures and bone mineral density (BMD) were investigated. The data were correlated with the CF phenotype [Shwachman Score (ShS), Chrispin-Norman Score (ChNS), and pulmonary function tests (PFT)]. RESULTS: The prevalence of joint pain in the CF patients was 12.9%, with a mean duration of 7 days. Swollen joints were found in 4 patients. None fulfilled the criteria for rheumatoid arthritis or connective tissue disease. Adult CF patients complained more often about noninflammatory back pain and myalgia, and demonstrated reduced spine mobility and impaired everyday life functions compared with the controls. Symptomatic CF patients had elevated erythrocyte sedimentation rate and C-reactive protein levels and performed worse on the ShS, ChNS, and PFT than asymptomatic patients. Antibodies against exotoxin A of Pseudomonas aeruginosa and recombinant Aspergillus fumigatus allergen f4 were found more frequently in CF patients with arthralgia. BMD was decreased in adult patients with more severe CF. CONCLUSION: In CF patients, the prevalence of rheumatic symptoms increases with age and CF severity. Our data suggest an association of infections with P. aeruginosa and A. fumigatus with the occurrence of rheumatic symptoms. However, no association of CF with definite inflammatory joint or connective tissue diseases was observed, and no CF-specific pattern of musculoskeletal symptoms was seen.
18662738 Dioscorea villosa (wild yam) induces chronic kidney injury via pro-fibrotic pathways. 2008 Sep Dioscorea villosa (wild yam) rhizome extract is a medicinal herb that is commonly used to treat symptoms of menopause and rheumatoid arthritis. We had evidence from previous in vitro experiments that this extract is toxic and pro-fibrotic in renal cells and aimed to test whether this occurs in vivo. Sprague-Dawley rats received 0.79g/kg/d D. villosa extract in their food or no treatment over 7, 14 and 28d (n=4 per group). Kidney and liver tissues were collected for protein extraction and Western immunoblots or fixed for special histologic stains, immunohistochemistry (IHC) and microscopy. Collagen deposition was assessed using Masson's trichrome staining and morphometry. Macrophage infiltration (ED-1), epithelial-to-mesenchymal transdifferentiation or activation of fibroblasts (vimentin, alpha-SMA), and pro-fibrotic growth factors (TGFss1, CTGF) were assessed using IHC. Protein expression levels of the pro-inflammatory cytokine, TNF-alpha, the pro-fibrotic transcription factor, NFkappaB, a measure of oxidative stress (heme oxygenase-1), alpha-SMA, vimentin and TGFss1 were determined. Results showed that kidneys of the treated animals had significantly increased collagen, vimentin, TGFbeta1, NFkappaB, EDI, CTGF and alpha-SMA by 28d. In the liver, there was increased ED-1 and TGFbeta1 in the centrilobular zone at 28d in treated animals. In conclusion, there was no acute reno- or hepato-toxicity associated with administration of D. villosa. However, there was an increase in fibrosis in the kidneys and in inflammation in livers of rats consuming D. villosa for 28 days. Long term supplementation with D. villosa may be best avoided, especially in people with compromised renal function and in those who need to take other drugs which may alter kidney function.
18644347 Celecoxib potently inhibits TNFalpha-induced nuclear translocation and activation of NF-ka 2008 Sep 1 Celecoxib is a specific inhibitor of cyclooxygenase 2 (COX2). While it has been used for the treatment of chronic inflammatory conditions, including rheumatoid arthritis, its detailed anti-inflammatory mechanism has not been clarified. Here, we found that Celecoxib potently inhibited TNFalpha-induced transcriptional activity and DNA binding activity of NF-kappaB; however, Celecoxib had no effect on TNFalpha-induced IKK activation and degradation of IkappaBalpha and IkappaBbeta, suggesting that it inhibited NF-kappaB activation via suppressing downstream of IKK activation and IkappaBs degradation. Interestingly, it was also found that Celecoxib abrogated TNFalpha-induced nuclear accumulation of the NF-kappaB p65 subunit. As a result, TNFalpha-induced expression of inflammatory cytokines, CXCL1/KC and CCL2/MCP-1, was clearly inhibited by Celecoxib. On the other hand, Celecoxib had no effect on the TNFalpha-induced nuclear translocation of c-jun and activation of ERK, JNK, p38 and Akt. Taken together, these data indicate that Celecoxib specifically inhibits TNFalpha-induced NF-kappaB activation at the level of its nuclear translocation. This negative regulation of NF-kappaB activation by Celecoxib might be an important mechanism leading to its anti-inflammatory activity.
18627208 Cigarette smoking and diffuse lung disease. 2008 Cigarette smoke, a toxic collection of more than 4000 chemicals generated from combustion of tobacco plant leaves, is known to cause several respiratory ailments, including chronic bronchitis, emphysema and lung cancer, and is associated with an increase in respiratory infections. In addition, cigarette smoking is considered a principal aetiological factor responsible for the development of certain diffuse interstitial and bronchiolar lung diseases, namely respiratory bronchiolitis-interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP) and adult pulmonary Langerhans' cell histiocytosis (PLCH). Although not exclusively seen in cigarette smokers, substantial clinical and epidemiological data support a central role for smoking as the primary causative agent of most RB-ILD, DIP and PLCH. Additional evidence in support of cigarette smoke as a primary aetiological agent in RB-ILD, DIP and PLCH is the observation that smoking cessation may lead to disease improvement, while recurrence of these disorders has been observed to occur in the transplanted lung upon re-exposure to tobacco smoke. Furthermore, histopathological changes of respiratory bronchiolitis, DIP and PLCH (with or without co-existent emphysema) may be found on lung biopsy in the same individual, implicating smoking as a common inciting agent of these diverse lesions. Recent studies also suggest a role for cigarette smoking as a potential co-factor in the development of acute eosinophilic pneumonia, usual interstitial pneumonia and rheumatoid arthritis-associated interstitial lung disease. In the current review, we propose a novel classification that takes into account the complex relationship between cigarette smoking and diffuse lung diseases. Investigation on the role of smoking as a potential causative factor or modifier of these diverse diffuse lung diseases is important, as smoking cessation utilizing state-of-the-art tobacco cessation efforts should be a central part of therapy, while pharmacotherapy with corticosteroids or other immune modifying agents should be reserved for selected patients.