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ID PMID Title PublicationDate abstract
24589726 Fibromyalgia in patients with other rheumatic diseases: prevalence and relationship with d 2014 Sep Fibromyalgia (FM) is a syndrome characterized by chronic widespread pain and the presence of specific tender points. The prevalence of FM has been estimated at 2-7 % of the general global population. The presence of FM in several rheumatic diseases with a structural pathology has been reported as 11-30 %. The objectives of this study were to determine the prevalence of FM and to evaluate the possible relationship between FM existence and disease activity among rheumatic diseases. The study group included 835 patients--197 rheumatoid arthritis (RA), 67 systemic lupus erythematosus (SLE), 119 ankylosing spondylitis (AS), 238 osteoarthritis (OA), 14 familial Mediterranean fever (FMF), 53 Behçet's disease (BD), 71 gout, 25 Sjögren's syndrome (SS), 20 vasculitis, 29 polymyalgia rheumatica (PMR), and two polymyositis (PM)--with or without FM. Recorded information included age, gender, laboratory parameters, presence of fatigue, and disease activity indexes. The prevalence of FM in patients with rheumatologic diseases was found to be 6.6 % for RA, 13.4 % for SLE, 12.6 % for AS, 10.1 % for OA, 5.7 % for BD, 7.1 % for FMF, 12 % for SS, 25 % for vasculitis, 1.4 % for gout, and 6.9 % for PMR. One out of two patients with PM was diagnosed with FM. Some rheumatologic cases (AS, OA) with FM were observed mostly in female patients (p = 0.000). Also, there were significant correlations between disease activity indexes and Fibromyalgia Impact Questionnaire scores for most rheumatologic patients (RA, AS, OA, and BD) (p < 0.05; respectively, r = 0.6, 0.95, 0.887, and 1). Concomitant FM is a common clinical problem in rheumatologic diseases, and its recognition is important for the optimal management of these diseases. Increased pain, physical limitations, and fatigue may be interpreted as increased activity of these diseases, and a common treatment option is the prescription of higher doses of biologic agents or corticosteroids. Considerations of the FM component in the management of rheumatologic diseases increase the likelihood of the success of the treatment.
24527796 VGX-1027 modulates genes involved in lipopolysaccharide-induced Toll-like receptor 4 activ 2014 Aug VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid] is a small molecule compound with immunomodulatory properties, which favourably influences the development of immuno-inflammatory and autoimmune diseases in different animal models such as type 1 diabetes mellitus, pleurisy, rheumatoid arthritis and inflammatory bowel disease. However, the precise mechanism of action of VGX-1027 remains to be ascertained. With this aim, we have studied the immunomodulatory effects of VGX-1027 in vitro, using a genome-wide oligonucleotide microarray approach, and in vivo, using the NZB/NZW F1 model of systemic lupus erythematosus. Microarray data revealed that the administration of VGX-1027 profoundly affected the immune response to exogenous antigens, by modulating the expression of genes that are primarily involved in antigen processing and presentation as well as genes that regulate immune activation. When administered in vivo VGX-1027 ameliorated the course of the disease in the NZB/NZW F1 mice, which correlated with higher per cent survival and improved clinical and histopathological signs. The data presented herein support the theory that VGX-1027 modulates immunity, probably by inhibiting inflammatory antigen presentation and so limiting immune cell expansion.
24456763 GUEPAR hinge knee prosthesis. 2014 Feb Early and late results of the GUEPAR hinge knee prosthesis were evaluated on a series of 184 operations performed before January 1st, 1974. There were 3 immediate deaths and 26 before 5 years. Nineteen prostheses were removed. One hundred and twenty-six knees had degenerative osteoarthritis, 52 rheumatoid arthritis. Twenty-two had been operated on before. Patellar displacement, present in 27% of the cases, was the most frequent cause of complaint: pain or instability, proportional to the severity of displacement, made re-operation necessary in 10% of the patients. Addition of a patellar prosthesis was the most successful treatment as far as pain is concerned: it is probably advisable as a primary procedure. Deep infections occurred in 8.3% of the cases, infrequently after 2 years. Healing was obtained in all cases either by revision or by removal and arthrodesis: but functional results were poor except when fusion was achieved, in half of the cases of arthrodesis. Loosening occurred in 16% of the cases, mainly as a consequence of inadequate technique. It was frequently tolerated: re-operation was necessary in 6% of the total. Late functional results were evaluated in 99 cases with a follow-up of 5 to 8 years. Apart from loosening, the results did not deteriorate. Sixty percent were evaluated as excellent or good, 29% fair, and 11% poor. In consideration of these results, the choice of this prosthesis should be limited to special cases. To prevent complications, the use of a patellar prosthesis, of reinforced models and of cementing under pressure is advisable.
24352680 TLR2 and TLR4 in autoimmune diseases: a comprehensive review. 2014 Oct Autoimmune diseases are immune disorders characterized by T cell hyperactivity and B cell overstimulation leading to overproduction of autoantibodies. Although the pathogenesis of various autoimmune diseases remains to be elucidated, environmental factors have been thought to contribute to the initiation and maintenance of auto-respond inflammation. Toll-like receptors (TLRs) are pattern recognition receptors belonging to innate immunity that recognize and defend invading microorganisms. Besides these exogenous pathogen-associated molecular patterns, TLRs can also bind with damage-associated molecular patterns produced under strike or by tissue damage or cells apoptosis. It is believed that TLRs build a bridge between innate immunity and autoimmunity. There are five adaptors to TLRs including MyD88, TRIF, TIRAP/MAL, TRAM, and SARM. Upon activation, TLRs recruit specific adaptors to initiate the downstream signaling pathways leading to the production of inflammatory cytokines and chemokines. Under certain circumstances, ligation of TLRs drives to aberrant activation and unrestricted inflammatory responses, thereby contributing to the perpetuation of inflammation in autoimmune diseases. In the past, most studies focused on the intracellular TLRs, such as TLR3, TLR7, and TLR9, but recent studies reveal that cell surface TLRs, especially TLR2 and TLR4, also play an essential role in the development of autoimmune diseases and afford multiple therapeutic targets. In this review, we summarized the biological characteristics, signaling mechanisms of TLR2/4, the negative regulators of TLR2/4 pathway, and the pivotal function of TLR2/4 in the pathogenesis of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, psoriasis, multiple sclerosis, and autoimmune diabetes.
24064020 Patient-driven assessment of disease activity in Behçet's syndrome: cross-cultural adapta 2013 May OBJECTIVES: The Behçet's Syndrome Activity Score (BSAS) is the first patient reported outcome measure developed to assess the global disease activity in patients with Behçet's syndrome (BS). We aimed to evaluate the reliability and validity of the Turkish version of BSAS for measuring disease activity in BS. We further investigated the performance of Routine Assessment of Patient Index Data (RAPID)3, a patient-reported index originally developed for rheumatoid arthritis, in BS patients. METHODS: Patients seen consecutively at a tertiary Rheumatology Centre were requested to complete BSAS and multidimensional health assessment questionnaire (MDHAQ). Besides, all attending physicians filled the Behçet's Disease Current Activity Form (BDCAF). Descriptive statistics and Pearson correlation coefficients were calculated accordingly for the reliability and validity assessments of BSAS. RESULTS: A total of 104 patients completed all three assessments. The test-retest reliability of BSAS has a good level (ICC=0.84, 95% CI [0.69-0.94]). The mean scores for BSAS, BDCAF and RAPID3 were 39±20.8, 3.2±1.4 and 9.2±5.6, respectively. BSAS was correlated with BDCAF moderately (r=0.587), while it was moderately correlated with RAPID3 (r=0.648). The correlation between the RAPID3 and BDCAF was moderate (r=0.403), but lower as compared to the correlations between the other instruments. CONCLUSIONS: We found that the BSAS has modest correlation with BDCAF and is a reliable and valid patient reported measure of disease activity that can be used to assess patients with BS. An outcome score composed of only patient-derived observations may have the additional advantage of being easier to use in a routine care setting. Demonstration of a moderate level of correlation between RAPID3 and BDCAF (close to the level of weak relationship), suggests that RAPID3 likely needs more investigations before recommending its use in BS.
24131352 Jakpot! New small molecules in autoimmune and inflammatory diseases. 2014 Jan Cytokines are key mediators of the development and homeostasis of haematopoietic cells, critical for host defense, but also for the development of autoimmune and inflammatory diseases such as psoriasis or rheumatoid arthritis (RA). Blocking cytokines activity by interfering with the ligand-receptor association has been successfully employed to treat several immune disorders. A subgroup of cytokines signals through receptors requiring the association with a family of cytoplasmic protein tyrosine kinases known as Janus kinases (Jaks). Jaks have recently gained significant attention as therapeutic targets in inflammation and autoimmunity, and several Jak inhibitory small molecules have been developed. The first two Jak inhibitors, tofacitinib and ruxolitinib, have been approved for the treatment of RA and primary myelofibrosis, respectively. Efficacy and safety data suggest that some of these oral Jak inhibitors as well as their topical formulations may soon enter the daily clinical practice for treating patients with psoriasis, lupus erythematosus or other inflammatory skin diseases. While biologics typically target one single cytokine, these new immunomodulators can inhibit signals from multiple cytokines intra-cellularly and therefore could be useful when other therapies are ineffective. Thus, Jak inhibitors may replace some traditional immunosuppressive agents and help patients not responding to previous therapies.
24089713 Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fi 2013 Sep 28 Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the entire cascade of aggregation intermediates formed along each pathway.
24063002 FOXP3⁺ T regulatory cell modifications in inflammatory bowel disease patients treated wi 2013 Treg modulation has been hypothesized as one of the mechanisms by which antitumor necrosis factor α (TNFα) agents exert their action in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, data in IBD are still conflicting. We evaluated CD4⁺CD25⁺FOXP3⁺ (Tregs) by flow cytometry in peripheral blood from 32 adult IBD patient before (T0) and after the induction of anti-TNFα therapy (T1). Eight healthy controls (HCs) were included. We also evaluated the number of FOXP3⁺ cells in the lamina propria (LP) in biopsies taken in a subset of patients and controls. Treg frequencies were significantly increased in peripheral blood from our patients after anti-TNFα therapy compared to T0. T1 but not T0 levels were higher than HC. The increase was detectable only in clinical responders to the treatment. A negative correlation was found among delta Treg levels and the age of patients or disease duration and with the activity score of Crohn's disease (CD). No significant differences were found in LP FOXP3⁺ cells. Our data suggest the possibility that in IBD patients the treatment with anti-TNFα may affect Treg percentages and that Treg modifications may correlate with clinical response, but differently in early versus late disease.
29320044 2013 Sep The purpose of this systematic review was to summarize the effects of task sharing for some selected procedures in hospitals. For four of the six procedures, we found no evidence that met our criteria for inclusion. Based on evidence assessed as being from low to very low quality we draw the following conclusions for two of six questions: What are the effects of task sharing between doctors and nurses for patients undergoing endoscopy? There may not be large differences for patient outcomes such as: pain/discomfort, gastrointestinal symptoms and quality of life. For the outcomes: need of assistance, duration, number of polyps missed, depth of sigmoidoscopy, number of biopsies, immediate complications and costs we cannot, on the basis of the evidence, determine whether there are important differences between endoscopy performed by nurses or by doctors. . What are the effects of task sharing between doctors and nurses for patients followed up in outpatient clinics? Patients with bronchiectasis: there may not be large differences in quality of life or the number of hospitalisations per patient. However, it is possible that there may be greater costs associated with the use of nurses. For the outcomes: lung function, lung capacity, exacerbations due to infection and training capacity we cannot, on the basis of the evidence, determine whether there are important differences for patients between follow-up by nurses or by doctors. Patients with asthma: there may not be large differences in quality of life, hospitalisation per patient or costs. For outcomes: number of symptom-free days, lung function, number of medication-free days, maximum air flow or the number of exacerbations we cannot, on the basis of the evidence, decide whether there are important differences for patients between follow-up by nurses or by doctors. Patients with rheumatoid arthritis: patient satisfaction may be somewhat improved due to follow-up by nurses rather than rheumatologists. For general health outcomes: joint pain, fatigue, global assessment of disease activity and disease activity measured by DAS 28 it is possible that there are no large differences between follow-up by nurses or by rheumatologists. Adults with cancer: nurses may use more time on consultation and take more blood tests, but there may not be large differences for patient satisfaction if cancer patients are followed up by a doctor or nurse. For the outcomes: mental health, depression, occurrence of metastases or overall costs we cannot, on the basis of the evidence, decide whether there are important differences for patients between follow-up by nurses or doctors.
23980209 T cell CD3ζ deficiency enables multiorgan tissue inflammation. 2013 Oct 1 Although a population of T cells with CD3ζ chain deficiency has been found in patients with systemic lupus erythematosus, rheumatoid arthritis, cancer, and infectious disease, the role of CD3ζ chain in the disease pathogenesis remains unknown. To understand the contribution of CD3ζ deficiency to the expression of organ injury, we have performed the following studies. We used CD3ζ-deficient mice to investigate the role of CD3ζ in the pathogenesis of organ tissue inflammation. We found that the CD3ζ(-/-) mice can spontaneously develop significant organ inflammation that can be accelerated following the administration of polyinosinic:polycytidylic acid or allogeneic cells (graft versus host). T cells from CD3ζ(-/-) mice display increased expression of the adhesion molecules CD44 and CCR2 and produce increased amounts of IFN-γ blockade, which mitigates tissue inflammation. Our results demonstrate that CD3ζ deficiency bestows T cells with the ability to infiltrate various tissues and instigate inflammation. Decreased CD3ζ expression noted in T cells from various diseases contributes independently to tissue inflammation and organ damage. Approaches to restore CD3ζ expression of the surface of T cells should be expected to mitigate tissue inflammation.
23924924 Invasion of histiocytic sarcoma into the spinal cord of HTLV-1 tax transgenic mice with HT 2013 Human T-cell leukemia virus type 1 (HTLV-1) can cause an aggressive malignancy known as adult T-cell leukemia/lymphoma (ATLL) as well as inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Transgenic (Tg) mice expressing HTLV-1 Tax also develop T-cell leukemia/lymphoma and an inflammatory arthropathy that resembles rheumatoid arthritis. We found that 8 of 297 Tax-Tg mice developed HAM/TSP-like disease with symmetrical paraparesis of the hind limbs, but these symptoms were absent in non-Tg littermates and in other mice strains at our animal facilities. We could perform detailed evaluations for five of these mice. These evaluations showed that the disease was not inflammatory, unlike that in HAM/TSP patients, but instead involved the invasion of histiocytic sarcoma cells into the lumbar spinal cord from the bone marrow where they had undergone extensive proliferation.
23861563 Therapeutic effects of the superoxide dismutase mimetic compound MnIIMe2DO2A on experiment 2013 Superoxide anion (O(2) (•-)) is overproduced in joint inflammation, rheumatoid arthritis, and osteoarthritis. Increased O(2) (•-) production leads to tissue damage, articular degeneration, and pain. In these conditions, the physiological defense against O(2) (•-), superoxide dismutases (SOD) are decreased. The Mn(II) complex MnL4 is a potent SOD mimetic, and in this study it was tested in inflammatory and osteoarticular rat pain models. In vivo protocols were approved by the animal Ethical Committee of the University of Florence. Pain was measured by paw pressure and hind limb weight bearing alterations tests. MnL4 (15 mg kg(-1)) acutely administered, significantly reduced pain induced by carrageenan, complete Freund's adjuvant (CFA), and sodium monoiodoacetate (MIA). In CFA and MIA protocols, it ameliorated the alteration of postural equilibrium. When administered by osmotic pump in the MIA osteoarthritis, MnL4 reduced pain, articular derangement, plasma TNF alpha levels, and protein carbonylation. The scaffold ring was ineffective. MnL4 (10(-7) M) prevented the lipid peroxidation of isolated human chondrocytes when O(2) (•-) was produced by RAW 264.7. MnL4 behaves as a potent pain reliever in acute inflammatory and chronic articular pain, being its efficacy related to antioxidant property. Therefore MnL4 appears as a novel protective compound potentially suitable for the treatment of joint diseases.
23837600 Tuberculosis: current state of knowledge: an epilogue. 2013 Oct Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has developed various mechanisms to survive and cause disease in the human host. Incomplete understanding of the complex microbe-host interactions has hindered the identification of suitable biomarkers to expedite the development of diagnostic tools, drugs and vaccines. The field effectiveness of directly observed therapy-short course has been compromised by the intrinsic limitations of sputum microscopy and suboptimal adherence to the long duration of treatment amid the HIV-TB syndemic and various socioeconomic constraints. While molecular tools are transforming the diagnostic processes, especially for multi-drug-resistant (MDR)-TB, drug development and service provision for MDR-TB seriously lag behind. Inappropriate management of detected MDR-TB cases may amplify drug resistance, jeopardizing future control. Targeted screening and treatment of latent infection with M. tuberculosis with the currently available immunodiagnostic tools and treatment regimens aim more for personal protection than major epidemiological impact or elimination. The interferon-γ release assays (IGRA) are not affected by cross-reaction to the bacillus Calmette-Guérin (BCG) vaccine and are increasingly used for such screening before initiation of biologics for treatment of rheumatoid arthritis and other autoimmune disorders. BCG offers only partial and unreliable protection against pulmonary TB in adults, the crucial transmission link for this airborne infection. Systems biology and vaccinomics may speed up vaccine research. The successful development of a fully effective TB vaccine that targets both growing bacteria and non-growing persisters may reflect a major breakthrough, as natural infection does not induce sufficient immunity to prevent reinfection.
23789712 Murine mPGES-1 3D structure elucidation and inhibitors binding mode predictions by homolog 2013 Jul 22 Microsomal prostaglandin E synthase-1 (mPGES-1) constitutes an inducible glutathione-dependent integral membrane protein that catalyzes the oxido-reduction of cyclooxygenase derived PGHâ‚‚ into PGEâ‚‚. mPGES-1 is an essential enzyme involved in a variety of human diseases or pathological conditions, such as rheumatoid arthritis, fever, and pain; it is therefore regarded as a primary target for development of next-generation anti-inflammatory drugs. Several compounds targeting human mPGES-1 have been reported in the literature. However, none of them is really specific for mPGES-1, and quite surprisingly, all of these compounds have very low or no activity against murine mPGES-1, making preclinical development hard and very expensive. In order to overcome this unresolved question, the current study focuses on the elucidation of the molecular determinants of murine mPGES-1 ligand binding modes combining protein homology modeling and site-directed mutagenesis approaches. We have developed, for the first time, two murine mPGES-1 models, describing both the closed and the open/active conformation of the enzyme. The 3D structure of human mPGES-1 having been recently disclosed, the main differences between the human and the murine enzyme models are described, emphasizing the smaller dimensions of the rodent substrate binding site, which could account for different activity of a ligand toward the two species. Furthermore, active binding modes are hypothesized, highlighting the most likely important residues for inhibition activity, whose identification is supported by in-house mutagenesis experiments. The results of our work could provide grounds for a rational structure-based drug design aimed to identify new inhibitors active against both human and murine mPGES-1.
23760648 Prevalence of metabolic syndrome in Behçet disease: a case-control study in Turkey. 2013 Oct BACKGROUND: Chronic inflammatory diseases such as psoriasis, rheumatoid arthritis, and inflammatory bowel diseases have been reported to be associated with the development of metabolic syndrome (MetS), which is characterized by central obesity, elevated triglycerides (TG), reduced high-density lipoproteins (HDL), impaired fasting blood glucose (FBG), and hypertension. Behçet disease (BD) is a chronic, immuno-inflammatory disease with multisystemic involvement. OBJECTIVE: The aim of this study was to investigate the prevalence and risk factors for MetS in patients with BD. METHODS: All patients had BD according to the criteria of the International Study Group. Diagnosis of MetS was established according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Mean waist circumference, body mass index (BMI), FBG, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total cholesterol, HDL, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), TG, systolic BP, and diastolic BP were measured and analyzed. RESULTS: A total of 86 patients and 72 healthy controls were included. MetS was detected in 35.4 % of patients and 20 % of controls (p = 0.04). Patients with BD had a 2.67-fold higher risk for MetS than healthy controls (p < 0.05). Significant risk factors for developing MetS according to multivariate analyses were BD, age, and BMI. Age at onset of the disease, duration of disease, BMI, gastrointestinal system involvement, and neurological involvement were correlated with increased MetS risk (p < 0.05). MetS tended to increase with age and the duration of the disease and was higher in women under the age of 40 years compared with healthy controls in the same age group. CONCLUSION: All BD patients should be closely monitored for hypertension, hyperlipidemia, and diabetes mellitus to avoid MetS development.
23752752 Preparation and evaluation of sustained release infliximab microspheres. 2013 May A sustained release microsphere system for an antibody (infliximab, molecular weight: 140 Kd) was formulated with PLGA 50:50 co-polymer using two methods of preparation: phase separation technique and double emulsion technique. Microspheres were made in triplicate using each technique and varying drug-to-polymer ratios. Drug-to-polymer ratio was maintained at 1:5, 1:10, or 1:20. In vitro release profile of infliximab was studied in phosphate-buffered saline solution at 37 °C. The release profile and encapsulation efficiency was compared between the two methods of preparation. The releases data was modeled by the sum of squares method to isolate the dominant release mechanism. The physical attributes of the microspheres prepared were characterized. The biochemical characteristics of infliximab before and after encapsulation were also evaluated by several analytical techniques such as size exclusion chromatography, isoelectric focusing, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biological activity of infliximab was also evaluated before and after encapsulation. The phase separation technique showed much higher entrapment efficiency than the double emulsion technique. Microspheres prepared using the double emulsion technique showed a longer release profile (∼5 days) compared to microspheres prepared using the phase separation technique (∼72 h). Physical and biochemical properties of infliximab did not change significantly after encapsulation into microspheres with either methods of preparation. Microspheres prepared using phase separation showed some loss in bioactivity. Based on this research it can be concluded that the microspheres can present an alternative delivery method for infliximab. LAY ABSTRACT: A sustained release microsphere system for an antibody (infliximab, molecular weight: 140 Kd) was formulated using polymers. This antibody is currently in the market for rheumatoid arthritis among various indications. Microspheres were made in triplicate using two techniques and varying drug-to-polymer ratios. Drug-to-polymer ratio was maintained at 1:5, 1:10, or 1:20. The release of drug from microsphere was studied. Biochemical properties of microspheres were also studied before and after encapsulation in microspheres. Various analytical techniques were used to study the biochemical properties of infliximab to ensure that it would be efficacious and safe after encapsulation. Sustained release of drug was observed from the microspheres. Infliximab showed no change in biochemical properties and also showed bioactivity. Based on this research it can be concluded that the microspheres can present an alternative delivery method for infliximab that is safe and efficacious and my result in cost savings for patients.
23496815 Airway epithelial cells initiate the allergen response through transglutaminase 2 by induc 2013 Mar 13 BACKGROUND: Transglutaminase 2 (TG2) is a post-translational protein-modifying enzyme that catalyzes the transamidation reaction, producing crosslinked or polyaminated proteins. Increased TG2 expression and activity have been reported in various inflammatory conditions, such as rheumatoid arthritis, inflammation-associated pulmonary fibrosis, and autoimmune encephalitis. In particular, TG2 from epithelial cells is important during the initial inflammatory response in the lung. In this study, we evaluated the role of TG2 in the pathogenesis of allergic asthma, particularly whether TG2 affects initial activation signaling leading to Th2 differentiation against antigens. METHODS: We induced allergic asthma by ovalbumin sensitization and intranasal challenge in wild-type (WT) BALB/c and TG2-deficient mice. Broncheoalveolar lavage fluid cells and intracellular cytokine production were analyzed by flow cytometry. Interleukin (IL)-33 and TG2 expression in lung epithelial cells was detected by confocal microscopy. RESULTS: Airway responsiveness was attenuated in TG2-deficient mice compared to that in the WT control. In addition, recruitment of eosinophils and Th2 and Th17 differentiation decreased in TG2-deficient mice. Treatment with cysteamine, a transglutaminase inhibitor, also reduced airway hypersensitivity, inflammatory cell recruitment, and T helper cell differentiation. TG2-deficient mice showed reduced IL-33 expression following induction of allergic asthma compared to those in the WT control. CONCLUSIONS: We found that pulmonary epithelial cells damaged by allergens triggered TG2-mediated IL-33 expression leading to type 2 responses by recruiting both innate and adaptive arms of the immune system.
23448480 Opioid receptors and their ligands in the musculoskeletal system and relevance for pain co 2013 Interest in opioid drugs like morphine, as the oldest and most potent pain-killing agents known, has been maintained through the years. One of the most frequent chronic pain sensations people experience is associated with pathological conditions of the musculoskeletal system. Chronic musculoskeletal pain is a major health problem, and an adequate management requires understanding of both peripheral and central components, with more attention drawn to the former. Intense experimental and clinical research activities resulted in important knowledge on the mechanisms and functions of the endogenous opioid system located in the periphery. This review describes the occurrence and distribution of endogenous opioids and their receptors in the musculoskeletal system, and their role in pain control in musculoskeletal disorders, such as rheumatoid arthritis and osteoarthritis. Using different techniques, including immunohistochemistry, electron microscopy or radioimmunoassay, expression of enkephalins, dynorphin, β-endorphin, and endomorphins was demonstrated in musculoskeletal tissues of animals and humans. Localization of opioid peptides was found in synovial membrane, periosteum, bone and bone marrow, loose connective tissue, the paratenon and musculotendinous junction of the achilles tendon. Animal and human studies have also demonstrated expression of µ, δ and κ opioid receptor proteins in musculoskeletal tissues using radioligand binding assays, autoradiography, electrophysiology, immunohistochemistry and Western blotting. Opioid receptor gene expression was reported based on polymerase chain reaction and in situ hybridization techniques. Combining morphological and quantitative approaches, important evidence that the musculoskeletal apparatus is equipped with a peripheral opioid system is provided. Demonstration of the occurrence of an endogenous opioid system in bone and joint tissues represents an essential step for defining novel pharmacological strategies to attain peripheral control of pain in musculoskeletal disorders.
23425281 Effects of infliximab and hydrocortisone on in vitro cytokine responses after stimulation 2013 Feb BACKGROUND: Both glucocorticosteroids and biologic drugs such as the tumor necrosis factor (TNF)-α antagonist infliximab are used often in the treatment of rheumatoid arthritis or inflammatory bowel disease. In severe disease, or if allergic reactions occur during treatment with infliximab, combined therapy with these drugs often is instituted. Combining infliximab and glucocorticosteroids may increase substantially the risk of severe opportunistic infections or dissemination of malignant tumors because of their additive effects as immunosuppressants. METHODS: In a whole-blood in vitro model, we studied the influence of different doses of infliximab and hydrocortisone, either separately or in combination, on the synthesis of selected cytokines after stimulation with lipopolysaccharide (LPS). RESULTS: Hydrocortisone in therapeutic serum concentrations significantly inhibited the expression of a majority of the cytokines tested. Infliximab, in serum concentrations relevant to clinical situations, inhibited TNF-α activity significantly. This effect was potentiated when infliximab was combined with hydrocortisone. Similar effects were found using a low dose of infliximab combined with hydrocortisone. Infliximab alone inhibited the expression of the cytokines interleukin (IL)-1 receptor antagonist, monocyte chemoattractant protein-1, IL-8, and IL-12. Hydrocortisone in combination with low-dose infliximab potentiated the suppressive effects on TNF-α, IL-1β, IL-8, and macrophage inflammatory protein-1α synthesis. CONCLUSIONS: Immune-modulating effects of infliximab were found both in clinically relevant doses and, most notably, in low doses reflecting serum concentrations found commonly in patients several months after the last injection. Infliximab potentiates the suppressive effects of hydrocortisone on cytokine synthesis.
23363068 Anti-obesity effects of galangin, a pancreatic lipase inhibitor in cafeteria diet fed fema 2013 May CONTEXT: Alpinia galanga Willd (Zingiberaceae) (AG) is a rhizomatous herb widely cultivated in shady regions of Malaysia, India, Indochina and Indonesia. It is used in southern India as a domestic remedy for the treatment of rheumatoid arthritis, cough, asthma, obesity, diabetes, etc. It was reported to have anti-obesity, hypoglycemic, hypolipidemic and antioxidant properties. OBJECTIVE: A flavonol glycoside, galangin, was isolated from AG rhizomes. Based on its in vitro pancreatic lipase inhibitory effect, the study was further aimed to clarify whether galangin prevented obesity induced in female rats by feeding cafeteria diet (CD) for 6 weeks. MATERIALS AND METHODS: The in vitro pancreatic lipase inhibitory effect of galangin was determined by measuring the release of oleic acid from triolein. For in vivo experiments, female albino rats were fed CD with or without 50 mg/kg galangin for 6 weeks. Body weight and food intake was measured at weekly intervals. On day 42, serum lipids levels were estimated and then the weight of liver and parametrial adipose tissue (PAT) was determined. The liver lipid peroxidation and triglyceride (TG) content was also estimated. RESULTS: The IC50 value of galangin for pancreatic lipase was 48.20 mg/mL. Galangin produced inhibition of increased body weight, energy intake and PAT weight induced by CD. In addition, galangin produced a significant decrease in serum lipids, liver weight, lipid peroxidation and accumulation of hepatic TGs. CONCLUSION: Galangin present in AG rhizomes produces anti-obesity effects in CD-fed rats; this may be mediated through its pancreatic lipase inhibitory, hypolipidemic and antioxidant activities.