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ID PMID Title PublicationDate abstract
20402635 Recent advances in the chemistry of phthalimide analogues and their therapeutic potential. 2010 Jul Phthalimide analogues have been extensively used in medicinal chemistry owing to their wide range of applications as anti-convulsant, anti-inflammatory, analgesic, hypolipidimic and immunomodulatory activities. Number of anti-inflammatory phthalimide analogues have been synthesized as tumor necrosis factor-alpha (TNF-alpha) inhibitors. TNF-alpha plays a critical role in certain physiological immune systems and its over-production causes severe damage to the host. It promotes the inflammatory response leading to many of the clinical problems associated with auto-immune disorders like rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis and refractory asthma. One of the phthalimide derivatives, LASSBio-468, was recently demonstrated to inhibit TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Its potential against chronic inflammatory diseases was also witnessed. Another derivative, DIMP, showed good anti-androgenic activity. These analogues have also been employed for the synthesis of several kinds of important therapeutic synthones. However extensive research on the chemistry and biological activities of phthalimide analogues have been carried out and number of reports appeared, a compilation focusing on chemistry and biological activity is still needed. This review, concisely describes the chemical and therapeutic aspects of phthalimide derivatives.
20383568 Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive d 2010 Aug Angiogenesis is a highly regulated physiological process that has been studied in considerable detail given its importance in several chronic pathologies. Many endogenous factors and hormones intervene in the regulation of angiogensis and classical as well as targeted drugs have been developed for its control. Angiogenesis inhibition has come off the bench and entered into clinical application for cancer therapy, particularly for metastatic disease. While the clinical benefit is currently in terms of months, preclinical data suggest that novel drugs and drug combinations could lead to substantial improvement. The many targets of endogenous angiogenesis inhibitors reflect the complexity of the process; in contrast, current clinical therapies mainly target the vascular endothelial growth factor system. Cancer chemopreventive compounds can retard tumor insurgence and delay or prevent metastasis and many of these molecules hinder angiogenesis, a mechanism that we termed angioprevention. Angiopreventive drugs appear to prevalently act through the inhibition of the pro-inflammatory and anti-apoptotic player NFkappaB, thus contrasting inflammation dependent angiogenesis. Relatively little is known concerning the effects of these angiogenesis inhibitors on gene expression of endothelial cells, the main target of many of these molecules. Here we provide an exhaustive list of anti-angiogenic molecules, and summarize their effects, where known, on the transcriptome and functional genomics of endothelial cells. The regulation of specific genes can be crucial to preventive or therapeutic intervention. Further, novel targets might help to circumvent resistance to anti-angiogenic therapy. The studies we review are relevant not only to cancer but also to other chronic degenerative diseases involving endothelial cells, such as cardiovascular disorders, diabetes, rheumatoid arthritis and retinopaties, as well as vessel aging.
20157029 Anetodermic primary cutaneous B-cell lymphoma: a unique clinicopathological presentation o 2010 Feb BACKGROUND: Primary cutaneous B-cell lymphoma manifested by anetoderma has been reported in 7 cases. In all, the secondary anetoderma developed in lesions of marginal-zone lymphoma or posttransplant lymphoproliferative disorder resembling marginal-zone lymphoma. The mechanisms underlying the destruction of elastic tissue in anetoderma are unclear. However, there is growing evidence linking primary anetoderma with a wide range of immunologic abnormalities, the most common being the presence of antiphospholipid antibodies. OBSERVATIONS: We analyzed data from 5 patients (3 male, 2 female) with clinical and histopathological features of anetodermic primary cutaneous B-cell lymphoma. Three had marginal-zone lymphoma and 2 had follicle-center cell lymphoma. In all, secondary anetoderma developed in self-regressing nodules/plaques of the lymphoma. Two patients also had lesions clinically and histopathologically compatible with primary anetoderma. Associated immunologic diseases were systemic lupus erythematosus-like disease and rheumatoid arthritis (1 patient each; not in patients with primary anetoderma). Antiphospholipid antibodies were found in 4 patients. CONCLUSIONS: Anetodermic primary cutaneous B-cell lymphoma is a rare and unique clinicopathological manifestation not only of marginal-zone lymphoma, as previously described, but also of follicle-center cell lymphoma. This type of secondary anetoderma, like primary anetoderma, might be associated with immunologic disorders, particularly antiphospholipid antibodies.
19950018 Novel functions of RANK(L) signaling in the immune system. 2010 The TNF family members RANKL and its receptor RANK have initially been described as factors expressed on T cells and dendritic cells (DCs), respectively, and have been shown to augment the ability of DCs to stimulate naive T cell proliferation and enhance DC survival. Since another, yet soluble receptor for RANKL, namely OPG, was initially characterized as a factor inhibiting osteoclast development and bone resorption, it was somewhat enigmatic at first why one and the same genes would be essential both for the immune system and bone development - two processes that on first sight do not have much in common. However, in a series of experiments it was conclusively shown that RANKL-expressing T cells can also activate RANK-expressing osteoclasts, and thereby in principal mimicking RANKL-expressing osteoblasts. These findings lead to a paradigm shift and helped to coin the term osteoimmunology in order to account for the crosstalk of immune cells and bone. More importantly was that these findings also provided a rationale for the bone loss observed in patients with a chronically activated immune system such as in rheumatoid arthritis, leukemias, or the like, arguing that T cells, which were activated during the course of the disease to fight it off, also express RANKL, which induces osteoclastogenesis and thereby shifts the intricate balance of bone deposition and resorption in favor of the latter. Through knockout mice it became also clear that the RANKL-RANK-OPG system is involved in other processes such as in controlling autoimmunity or immune responses in the skin. We will briefly summarize the role of RANK(L) signaling in the immune system before we discuss some of the recent data we and others have obtained on the role of RANK(L) in controlling autoimmunity and immune responses in the skin.
19743552 The inflammatory reflex and the role of complementary and alternative medical therapies. 2009 Aug The body's first defense against invading pathogens or tissue injury is the innate immune system. Since excessive immune responses can be damaging, anti-inflammatory mechanisms function to control the pro-inflammatory response and prevent injury. The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response. Knowledge concerning innervation of the immune system offers a unique opportunity to explore previously unrecognized techniques to treat disease. It also enables consideration of the neurological basis of complementary and alternative medical therapies, such as meditation and acupuncture. This evolving area of research has implications for the pathogenesis of chronic inflammatory conditions including inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes, and other conditions of excessive cytokine release.
19710437 Risk of osteonecrosis of the jaw in cancer patients taking bisphosphonates. 2009 Sep 1 PURPOSE: The risk of osteonecrosis of the jaw (ONJ) associated with bisphosphonate use in patients with cancer is reviewed. SUMMARY: ONJ is a relatively new complication of supportive care in cancer. Bisphosphonate-associated ONJ can be generally defined as necrotic bone exposure to the oral cavity and inflammatory reactions of the surrounding soft tissue in patients receiving bisphosphonates but not radiotherapy to the head and neck. The risk of development of ONJ varies with the type of bisphosphonate used and the duration of exposure, with more potent agents increasing the risk with shorter durations of exposure. From the current evidence, the incidence of this disorder in cancer patients receiving bisphosphonates can be as high as 10% when patients have more than one risk factor. Risk factors include type of bisphosphonate, duration of exposure, concomitant medications, comorbidities (e.g., hypertension, dyslipidemia, diabetes, rheumatoid arthritis, lupus), and lifestyle behaviors (e.g., smoking, obesity). To minimize the risk of ONJ, patients initiated on bisphosphonates should optimize routine dental care and have their baseline oral cavity status evaluated by both clinical and radiographic examinations before initiation of bisphosphonate therapy. Current management of ONJ is difficult and empirical. At present, a conservative approach is recommended, including systemic antibiotics, antiseptic oral rinses, pain control, and limited debridement. CONCLUSION: Cancer patients receiving bisphosphonates are at risk for developing ONJ. Clinicians should evaluate patients' oral integrity and existing risk factors before initiating bisphosphonate therapy. Once treatment is started, patients should be closely monitored for signs and symptoms of ONJ.
19685415 Recreational exercise in rheumatic diseases. 2009 Nov The purpose of this study was to evaluate changes in health-related quality of life after eight to twelve months of recreational exercise in patients with rheumatic diseases (inflammatory joint disease, osteoarthritis, fibromyalgia and other generalized pain syndromes), and to determine whether patient (age, sex, diagnosis) and exercise characteristics (follow-up time, type of activity, frequency of participation) are related to health-related quality of life change. Health-related quality of life was assessed twice in 138 patients with rheumatic diseases. 1) At enrolment in a centre for outpatient recreational exercise and 2) following eight to twelve months of recreational exercise. Health-related quality of life was measured using the Short-Form Health Survey 36 and three numeric rating scales for pain, fatigue and general condition. Multiple linear regression was used to analyze the influence of patient and exercise characteristics on follow-up HRQoL-score. Patients showed significant improvements in pain and general condition, and reported a positive change in health. A diagnosis of inflammatory joint disease (e. g. rheumatoid arthritis, polyarthritis, spondylitis) or osteoarthritis, participating in sports activities two to three times per week, and following land-based fitness classes were associated with the most improvement in health-related quality of life. Regular participation in recreational exercise contributes to improved health-related quality of life in patients with rheumatic diseases.
19643665 The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. 2009 Aug Nuclear factor (NF)-kappaB has an important role in immunity and inappropriate NF-kappaB activity has been linked with many autoimmune and inflammatory diseases. Multiple mechanisms normally ensure the proper termination of NF-kappaB activation. In this context, the intracellular ubiquitin-editing protein A20 (also known as Tumor Necrosis Factor Alpha-Induced Protein 3 or TNFAIP3) is a key player in the negative feedback regulation of NF-kappaB signaling in response to multiple stimuli. Moreover, A20 also regulates tumor necrosis factor (TNF)-induced apoptosis. Recent genetic studies demonstrate a clear association between several mutations in the human A20 locus and immunopathologies such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and type 1 diabetes. These findings further illustrate the importance of A20 in the resolution of inflammation and the prevention of human disease.
19634279 [Osteoporosis: whom, when and how to treat?]. 2009 Osteoporosis is a chronic disease of mass appearance and should be defined as a disease of decreased bone strength rather than a disease of decreased bone mass. Osteoporosis related fractures are of particular interest due to their high burden on the individual and society and also their importance as a target of pharmacological intervention. Bone mineral measurement (BMD), which is an established tool to diagnose osteoporosis (W.H.O., 1994) is not sufficient as a tool for treatment decisions. Currently, assessment of quality of bone is costly, technically demanding and/or invasive. In clinical practice, the W.H.O. recommendation (2007) enables a more advantageous assessment of individual absolute risk of fracture based on BMD and clinical risk factors independent of BMD (sex, age, prevalent fracture, parent fractured hip, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, smoking, and excessive alcohol intake). Modern regimens of anticatabolic (antiresorption) therapies not only maintain bone microarchitecture but enable a sufficient bone renewal in majority of patients. However, even with anticatabolic treatments, aging is associated with decrease in new bone formation and mechanical competence of bone. Performance of bone osteoblasts and osteocytes, bone volume and quality and architecture of bone is improved in patients treated with bone anabolic agents. Teriparatide treatment considerably reduces risk of vertebral and nonvertebral fracture, back pain and different aspects of quality of life. However, use of the bone anabolic drugs is limited to 18-24 months. To prevent subsequent increase in risk of fracture, sequential treatments with anabolic and anti-catabolic drugs offer benefits needed for the long-term compliance. In conclusion, selection of drugs with the highest antifracture efficacy should be guided by the underlying mechanisms of osteoporosis, and by expectations of the treatment (safety and efficacy). Anti-catabolic drugs are most appropriate in patients with high bone turnover. Anabolic treatment is indicated in patients with low bone formation in the elderly, in glucocorticoid induced osteoporosis, and where preservation of bone mass and bone architecture by anti-catabolic drugs is not sufficient to efficiently reduce high absolute risk of fracture.
19555305 Gastroresistant microcapsules: new approaches for site-specific delivery of ketoprofen. 2009 Jan Ketoprofen is a potent non-steroidal anti-inflammatory drug (NSAID) that has been widely used in the treatment of rheumatoid arthritis and other related conditions. However, it carries the risk of undesirable systemic side effects and gastrointestinal irritation at the usual dose of oral administration. The aim of this study was to prepare and evaluate gastroresistant microcapsules containing ketoprofen. Microcapsules were obtained by a spray-drying process starting from an O/A emulsion in the presence of different pH-dependent materials (Eudragit L100, Eudragit S100, and stearic acid) dissolved in the external phase. The influence of formulation factors (oily phase employed for drug solubilization, type of coating) on the morphology, particle size distribution, drug loading capacity, in-vitro release, and ex-vivo permeation characteristics were investigated. Drug loading capacity was very high for all the microcapsules prepared. Formulation factors did not significatively influence the mean particle size, but modified microcapsule in-vitro and ex-vivo behavior.
19373468 A comparison of four different HRQoL generic questionnaire in five different patient group 2009 Nov Most of musculoskeletal diseases involve pain and reduced physical functioning. Recognition of the coexistence of more than one musculoskeletal disease is important because they are relatively common and has a substantial impact on health-related quality of life (HRQoL). Our aim was to compare the results of four generic QoL questionnaires--QoL-5, Nottingham Health Profile (NHP), Short Form (SF)-6D, and Visual Analogue Scale (VAS)--in five different patient groups. Two hundred and one patients representing five different disease groups (knee osteoarthritis, osteoporosis, back pain, rheumatoid arthritis and ankylosing spondylitis), randomly selected through the Ankara Numune Education and Research Hospital Physical Medicine and Rehabilitation Outpatient Clinic, were included in the study. Scores indicating low QoL for each of the five diseases compared are reported. Patients in each disease group stated high disability. No strong correlation between any of the scales could be determined, and NHP was identified as the only scale able to differentiate between the diseases. Many instruments are available for measuring HRQoL. The QoL-5, NHP, SF-6D, and VAS are four commonly used generic (i.e., not disease-specific) measures for quantifying HRQoL in patients with musculoskeletal disorders. Most studies have focused on only one musculoskeletal disease, but comorbidity of musculoskeletal disorders is common. We emphasize in this study the effect of multiple musculoskeletal diseases on HRQoL.
19326066 [In situ assembly of a modular noncemented total shoulder prosthesis for the reconstructio 2009 Mar OBJECTIVE: Exact restoration of the glenohumeral joint, especially in the case of complex pathologies, due to high prosthesis modularity and in situ assembly; later conversion to inverse design with same shaft possible. INDICATIONS: Primary shoulder osteoarthritis, secondary joint destruction after previous fracture or its treatment, humeral head necrosis, or inflammatory processes, revisions of defect situations such as hemiprostheses. CONTRAINDICATIONS: General contraindications of total shoulder arthroplasty, additionally, functional loss of the rotator cuff, advanced osteoporosis, narrow medullary canal, e.g., in patients with juvenile rheumatoid arthritis. SURGICAL TECHNIQUE: After deltopectoral approach free resection of the humeral head along landmarks, stepwise rasping of the humeral medullary canal, insertion of the rectangled stem, realignment of humeral height with the body, realignment of inclination and possible retroversion with the inclination set. The asymmetric head ensures exact restoration of the joint center. Implantation of the cemented glenoid, test of range of motion and soft-tissue tension, and exchange of components in situ, if necessary. RESULTS: A prospective evaluation of the first 146 consecutive patients with 1-year follow-up revealed significant improvements of about 151% regarding pain and of about 98% in function without significant differences between different indications. Four shaft fissures were observed and treated with intraoperative cerclages during the learning period. No further fissures were noted after adaptation of the surgical procedure and subsequent guidelines. One traumatic and one atraumatic head rotation were observed but should be prevented with a new torque wrench. Similar functional results can be achieved even in complex shoulder pathologies due to the high modularity of the prosthesis.
19287931 [Vaccination against yellow fever among patients on immunosuppressors with diagnoses of rh 2009 Jan Yellow fever is endemic in some countries. The anti-yellow fever vaccine is the only effective means of protection but is contraindicated for immunocompromised patients. The aim of this paper was to report on a case series of rheumatological patients who were using immunosuppressors and were vaccinated against this disease. This was a retrospective study by means of a questionnaire applied to these patients, who were vaccinated 60 days before the investigation. Seventy patients of mean age 46 years were evaluated. Most of them were female (90%). There were cases of rheumatoid arthritis (54), systemic lupus erythematosus (11), spondyloarthropathy (5) and systemic sclerosis (2). The therapeutic schemes included methotrexate (42), corticosteroids (22), sulfasalazine (26), leflunomide (18), cyclophosphamide (3) and immunobiological agents (9). Sixteen patients (22.5%) reported some minor adverse effect. Among the eight patients using immunobiological agents, only one presented a mild adverse effect. Among these patients using immunosuppressors, adverse reactions were no more frequent than among immunocompetent individuals. This is the first study on this topic.
19184347 Inhibition of neutrophil infiltration by a malleable protein matrix of lactic acid bacteri 2009 Mar OBJECTIVE: A novel nutraceutical ingredient, the Malleable Protein Matrix (MPM), has previously demonstrated a significant anti-inflammatory effect in a systemic inflammatory disease model, comparable to conventional drugs. The objective of this study was to investigate the potential anti-inflammatory effects of MPM on neutrophil infiltration in vivo, phagocytosis activity as well as cytokine and chemokine production. METHODS: Groups of ten C57BL6J mice received water or MPM per os for a period of 2 weeks prior to the creation of a murine air pouch. The subsequent neutrophil recruitment and activities were characterized following lipopolysaccharide injection. RESULTS: In the water control group, the number of recruited cells was 1.8X10(7) cells/pouch, which was reduced to 9X10(6) cells/pouch with oral MPM consumption, representing an inhibition of 50% of infiltrating leukocytes. A considerable reduction in the cytokine and chemokine production, mostly TNFalpha, IL-1beta and IL-6 production in the MPM-treated group, suggested an inhibition of the mediators responsible for leukocyte extravasation. On the other hand, MPM consumption had no effect on neutrophil phagocytosis activity. CONCLUSION: MPM administration demonstrates a significant reduction of neutrophil infiltration associated with an inhibition of cytokine and chemokine production. The air pouch model shares similarities with in vivo characteristics of rheumatoid arthritis and neutrophilic diseases, both of which would benefit from this 50% inhibition of neutrophil infiltration induced by MPM.
19149741 Targeting hypoxia-inducible factor-1 (HIF-1) signaling in therapeutics: implications for t 2009 Jan In response to hypoxia, adaptive hypoxia-inducible factor-1 (HIF-1) signaling events are activated to increase oxygen transport, anaerobic energy production and protective pathways to minimize ischemic tissue damage. Although the activation and subsequent induction of gene transcription by HIF-1 is normally associated with hypoxia, it is now established that HIF-1 signaling can be triggered under inflammatory conditions. HIF-1 has been implicated in a number of inflammatory diseases including rheumatoid arthritis, allergic asthma, psoriasis and inflammatory bowel disease (IBD). In the gastrointestinal tract, HIF-1-regulated gene products, such as vascular endothelial growth factor, intestinal trefoil factor and CD73, have been shown to provide protection in animal models of intestinal inflammation. Given the importance of HIF-1 signaling in the aforementioned diseases, there exists considerable interest in the development of methods to modulate HIF-1 expression as well as down-stream signaling events. This review examines HIF-1 signaling with a special focus on the gastrointestinal tract. The patents pertaining to the modulation of HIF-1 signaling are summarized, and their relevance to the treatment of inflammatory bowel disease is discussed.
19145554 Ginsenoside Rp1, a ginsenoside derivative, blocks lipopolysaccharide-induced interleukin-1 2009 Mar Ginsenoside Rp1 (G-Rp1) is a ginseng saponin derivative with chemopreventive and anti-cancer activities. In this study, we examined the regulatory activity of G-Rp1 on the production of interleukin (IL)-1beta, a pro-inflammatory cytokine managing acute or chronic inflammatory diseases such as septic shock and rheumatoid arthritis, from lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. G-Rp1 dose-dependently inhibited IL-1beta production from LPS-treated RAW264.7 cells without altering cell viability. This compound suppressed both mRNA and protein levels of IL-1beta. In particular, this compound was found to down-regulate phosphorylation of the inhibitor of kappaB (IkappaB) kinase (IKK)/IkappaBalpha, and consequent activation of NF-kappaB, but not the activation of its upstream signaling enzymes such as mitogen-activated protein kinases (MAPK) and p85, a regulatory subunit of phosphoinositide 3-kinase (PI3K). Therefore, these results suggest that G-Rp1 may act as an inhibitor of IL-1beta production by inhibiting the NF-kappaB pathway.
21484156 Curcumin synergizes with resveratrol to stimulate the MAPK signaling pathway in human arti 2011 May The mitogen-activated protein kinase (MAPK) pathway is stimulated in differentiated chondrocytes and is an important signaling cascade for chondrocyte differentiation and survival. Pro-inflammatory cytokines such as interleukin 1β (IL-1β) play important roles in the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA). In this study, we investigated whether curcumin and resveratrol can synergistically inhibit the catabolic effects of IL-1β, specifically the inhibition of the MAPK and subsequent apoptosis in human articular chondrocytes. Chondrocytes were either left untreated or treated with 10 ng/ml IL-1β or 1 μM U0126, a specific inhibitor of MAPK pathway alone for the indicated time periods or pre-treated with 10 μM curcumin, 10 μM resveratrol or 10 μM resveratrol and 10 μM curcumin for 4 h followed by co-treatment with 10 ng/ml IL-1β or 1 μM U0126 and 10 μM resveratrol, 10 μM curcumin or 10 μM resveratrol and 10 μM curcumin for the indicated time periods. Cultures were evaluated by immunoblotting and transmission electron microscopy. Incubation of chondrocytes with IL-1β resulted in induction of apoptosis, downregulation of β1-integrins and the extracellular signal-regulated kinase 1/2 (Erk1/2). Interestingly, U0126 induced apoptosis and blocked the above-mentioned proteins in a similar way to IL-1β. Furthermore, curcumin and resveratrol inhibited IL-1β- or U0126-induced apoptosis and downregulation of β1-integrins and Erk1/2 in human articular chondrocytes. These results suggest that combining these two natural compounds activates MEK/Erk signaling, a pathway that is involved in the maintenance of chondrocyte differentiation and survival.
21197088 Is musculoskeletal ultrasonography an operator-dependent method or a fast and reliably tea 2010 Objectives. To assess interreader agreements and a learning curve between three (senior, junior, and beginner) different experienced musculoskeletal ultrasonographers. Senior served as the imaging "gold standard". Methods. Clinically dominant joints (finger, shoulder, knee, tibiotalar, and talonavicular) of 15 rheumatoid arthritis (RA) patients were examined by three different experienced ultrasonographers (senior 10 years, junior 10 months, and beginner one month). Each patient's ultrasonographic findings were reported unaware of the other investigators' results. κ coefficients, percentage agreements, sensitivities, and specificities were calculated. Results. 120 joints of 15 RA patients were evaluated. Comparing junior's and beginner's results each to the senior's findings, the overall κ for all examined joints was 0.83 (93%) for junior and 0.43 (76%) for beginner. Regarding the different joints, junior's findings correlate very well with the senior's findings (finger joints: κ = 0.82; shoulder: κ = 0.9; knee: κ = 0.74; tibiotalar joint: κ = 0.84; talonavicular joint: κ = 0.84) while beginner's findings just showed fair to moderate agreements (finger joints: κ = 0.4; shoulder: κ = 0.42; knee: κ = 0.4; tibiotalar joint: κ = 0.59; talonavicular joint: κ = 0.35). In total, beginner's results clearly improved from κ = 0.34 (agreement of 67%) at baseline to κ = 0.78 (agreement of 89%) at the end of the evaluation period. Conclusions. Ultrasonographic evaluation of a ten-month-experienced investigator in comparison to a senior ultrasonographer was of substantial agreement. Agreements between a beginner and a highly experienced ultrasonographer were only fair at the beginning, but during the study including ultrasonographical sessions of 15 RA patients, the beginner clearly improved in musculoskeletal ultrasonography.
21733202 NSAIDs. 2010 Jun 28 INTRODUCTION: NSAIDs are widely used. Almost 10% of people in The Netherlands used a non-aspirin NSAID in 1987, and the overall use was 11 defined daily doses per 1000 population a day. In Australia in 1994, overall use was 35 defined daily doses per 1000 population a day, with 36% of the people receiving NSAIDs for osteoarthritis, 42% for sprain and strain or low back pain, and 4% for rheumatoid arthritis; 35% of the people receiving NSAIDs were aged over 60 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: Are there any important differences between oral NSAIDs? What are the effects of topical NSAIDs; and of co-treatments to reduce the risk of gastrointestinal adverse effects of oral NSAIDs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 36 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the benefits and harms of the following interventions: differences in efficacy among different oral NSAIDs, between oral and topical NSAIDs, and between oral NSAIDs and alternative analgesics; dose-response relationship of oral NSAIDs; and H(2) blockers, misoprostol, or proton pump inhibitors to mitigate gastrointestinal adverse effects of oral NSAIDs.
19641515 Significance of the S100A4 protein in psoriasis. 2010 Jan The S100A4 protein is reported as a pivotal player in the tumor microenvironment with a metastasis-promoting function. Moreover, the upregulation of S100A4 is found in other non-malignant human disorders as cardiac and pulmonary systems and rheumatoid arthritis. In this study, we investigated the expression and significance of S100A4 in psoriasis. We found significant upregulation of S100A4 in the dermis of psoriatic skin compared with normal skin. This pattern of S100A4 expression differs considerably from that of other S100 proteins, S100A7 and S100A8/9, with predominant expression in the epidermis of psoriasis. Furthermore, we revealed a massive release of the biologically active forms of S100A4 from psoriatic skin. Interestingly, we found stabilization (increase) of p53 in the basal layer of epidermis in close proximity to cells expressing S100A4. To examine the possible implication of S100A4 in the pathogenesis of psoriasis, we analyzed the effect of S100A4 blocking antibodies in a human psoriasis xenograft SCID mouse model and observed a significant reduction of the epidermal thickness and impairment in cell proliferation and dermal vascularization. In conclusion, we showed strong upregulation and release of S100A4 in the upper dermis of psoriatic skin and found evidence indicating that S100A4 might actively contribute to the pathogenesis of psoriasis.