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ID PMID Title PublicationDate abstract
20299265 Continuous at-home postoperative analgesia using a catheter in the case of hand surgery: p 2010 Apr In hand surgery, ever since continuous at-home postoperative analgesia (CPA) was implemented, procedures which cause pain for more than 24h can now be performed in ambulatory surgery. The aim of our work was to study the feasibility of CPA. Our series comprised 40 patients with a mean age of 50 years. Twenty-four patients had an ASA score of 1 and 16 patients had an ASA score of 2. Indications were osteoarthritis and rheumatoid diseases. Three steps were involved: preoperative (patient screening and information), peroperative (placement of a peripheral nerve catheter through an axillary approach using an elastomeric device) and postoperative (at-home patient care provided by visiting nurses). Evaluation was rated using a CPA score (0 to 10) based on analgesia quality and network organization data. The global CPA score was 1.85. The quality of analgesia (2.6) scored less than the quality of organization (1.1). In the case of analgesia, sleep obtained the lowest score, followed by pain, and lastly, unwanted events. As far as organization was concerned, the network obtained the lowest score, followed by patient satisfaction, and lastly, patient information. Problems were encountered due to insufficient nurse training, analgesia failures, as well as unwanted events related to the oral antalgic treatment. However, technical success was almost always achieved. Our results show that the indications for ambulatory surgery could be extended and hospital-private practice networks be further developed. CPA appears to be a promising technique for analgesia and ambulatory surgery.
21177290 Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti 2011 Apr BACKGROUND: Anti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs). OBJECTIVE: To describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors. METHODS: A 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case-control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease. RESULTS: 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p<0.0001)or adalimumab (OR=10.0 (2.3 to 44.4); p=0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002). CONCLUSION: Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI.
20962324 Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse re 2011 Jan 13 Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10-competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10-competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24(hi)CD27(+) B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10-dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease.
20110006 Changes in physicians' practice of prescribing cyclooxygenase-2 inhibitor after market wit 2009 Nov BACKGROUND: Safety concerns regarding severe cardiovascular events associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors resulted in the market withdrawal of rofecoxib in September 2004. OBJECTIVE: Using Taiwan's National Health Insurance 2003-;2004 claims database, this population-based retrospective cohort study assessed changes in physicians' practice of prescribing a COX-2 inhibitor after market withdrawal of rofecoxib. METHODS: Patients with rheumatoid arthritis (RA) or osteoarthritis (OA) who were chronic users of COX-2 inhibitors before market withdrawal of rofecoxib were identified. Eligible chronic users of COX-2 inhibitors were patients who received >or=3 consecutive prescriptions for celecoxib or rofecoxib to treat RA or OA between April 1 and September 30, 2004. The main outcome evaluated in this study was the volume of celecoxib prescribing for each patient by his or her prescribing physician at the first postwithdrawal outpatient visit related to RA or OA. For each matched physician, we calculated the prescribing practice indexes before and after the withdrawal of rofecoxib to assess changes in prescribing practice. A higher value of the index represented less potential that patients with a history of cardiovascular events who were seen by a physician received a prescription for a COX-2 inhibitor. A 2-stage model analysis was used to assess changes, in physicians' prescribing practice after rofecoxib's withdrawal, in the volume of prescribing a COX-2 inhibitor for each matched patient by his or her prescribing physician. RESULTS: Of the chronic users of COX-2 inhibitors identified, 13,101 were taking celecoxib and 8763 were taking rofecoxib before rofecoxib was withdrawn from the market. Concerns about safety after the mar- ket withdrawal of rofecoxib reduced physicians' volume of prescribing a COX-2 inhibitor, particularly in patients who had previously received rofecoxib. After rofecoxib's withdrawal, 72.50% of previous rofecoxib users (n = 6353) and 49.50% of previous celecoxib users (n = 6485) stopped taking COX-2 inhibitors. Only 27.50% of the rofecoxib users (n = 2410) were switched to celecoxib after rofecoxib's withdrawal. Overall, physicians' prescribing practice for celecoxib increased, from baseline to 3 months after rofecoxib's withdrawal, from 0.66 to 0.79 for academic medical center physicians, 0.71 to 0.82 for metropolitan hospital physicians, 0.77 to 0.88 for local community hospital physicians, and 0.86 to 0.92 for primary care clinic physicians. After controlling for patients' demographics, the linear regression analysis revealed that changes in physicians' prescribing practice after the withdrawal of rofecoxib affected the volume of prescribing a COX-2 inhibitor (P < 0.001). CONCLUSIONS: The volume of celecoxib prescribing was greatly reduced after rofecoxib was withdrawn from the market. Physicians' prescribing practice for COX-2 inhibitors significantly changed after the withdrawal, and it had a significant impact on the postwithdrawal volume of celecoxib prescribing.
19530990 Syk: a novel target for treatment of inflammation in lung disease. 2009 Jun Spleen Tyrosine Kinase (Syk) is widely expressed in the immune system and functions in the transmission of inflammatory signals via ITAM-bearing cell surface receptors. The broad expression pattern and importance of Syk in regulating innate immunity and the inflammatory response have led to significant interest from the pharmaceutical industry to developing anti-Syk therapeutics for the treatment of inflammatory disorders such as allergic rhinitis and rheumatoid arthritis. While the function and regulation of Syk has been well-described in leukocytes, where its primary role is an early transducer of signaling following immunoreceptor engagement, Syk has recently been described in non-immune cells, such as the airway epithelium, that also play an important role in mediating the inflammatory response. This manuscript will focus on the expression and function of Syk in the context of inflammatory lung diseases, and review recent data that have demonstrated novel roles for Syk in airway epithelial cells, particularly its role in mediating the human rhinovirus (HRV) induced inflammatory response and viral cell entry. In addition, data describing the efficacy of novel Syk inhibitors in the management of inflammatory diseases in animal models and early clinical trials are also reviewed.
21047980 Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone mar 2011 Jan 1 PURPOSE: The graft-versus-tumor (GVT) effect is a potent form of immunotherapy against many hematologic malignancies and some solid tumors. The beneficial GVT effect after allogeneic bone marrow transplantation (BMT) is tightly linked to its most significant complication, graft-versus-host disease (GVHD). The role of interleukin-6 (IL-6) after allogeneic BMT is not well understood. This study used a series of complementary knockout and antibody blockade strategies to analyze the impact of IL-6 in multiple clinically relevant murine models of GVHD and GVT. EXPERIMENTAL DESIGN: We examined the effect of the source of IL-6 by analyzing the role IL-6 deficiency in donor T cells, donor bone marrow or in host tissues. We confirmed and extended the relevance of IL-6 deficiency on GVHD and GVT by treating BMT recipients with anti-mouse IL-6 receptor (IL-6R), MR16-1. RESULTS: Deficiency of IL-6 in donor T cells led to prolongation of survival. Total inhibition of IL-6 with MR16-1 caused an even greater reduction in GVHD-induced mortality. The reduction in GVHD was independent of the direct effects on T effector cell expansion or donor regulatory T cells. GVT responses were preserved after treatment with MR16-1. CONCLUSION: MR16-1 treatment reduced GVHD and preserved sufficient GVT. Tocilizumab, a humanized anti-IL-6R monoclonal antibody (mAb), is approved in several countries including the United States and European Union for the treatment of rheumatoid arthritis and other inflammatory diseases. Blockade of IL-6 with anti-IL-6R mAb therapy may be testable in clinical trials as an adjunct to prevent GVHD in BMT patients without a significant loss of GVT.
20231688 Relative over-reactivity of human versus chimpanzee lymphocytes: implications for the huma 2010 Apr 15 Although humans and chimpanzees share >99% identity in alignable protein sequences, they differ surprisingly in the incidence and severity of some common diseases. In general, humans infected with various viruses, such as HIV and hepatitis C virus, appear to develop stronger reactions and long-term complications. Humans also appear to suffer more from other diseases associated with over-reactivity of the adaptive immune system, such as asthma, psoriasis, and rheumatoid arthritis. In this study, we show that human T cells are more reactive than chimpanzee T cells to a wide variety of stimuli, including anti-TCR Abs of multiple isotypes, l-phytohemagglutin, Staphylococcus aureus superantigen, a superagonist anti-CD28 Ab, and in MLRs. We also extend this observation to B cells, again showing a human propensity to react more strongly to stimuli. Finally, we show a relative increase in activation markers and cytokine production in human lymphocytes in response to uridine-rich (viral-like) ssRNA. Thus, humans manifest a generalized lymphocyte over-reactivity relative to chimpanzees, a finding that is correlated with decreased levels of inhibitory sialic acid-recognizing Ig-superfamily lectins (Siglecs; particularly Siglec-5) on human T and B cells. Furthermore, Siglec-5 levels are upregulated by activation in chimpanzee but not human lymphocytes, and human T cell reactivity can be downmodulated by forced expression of Siglec-5. Thus, a key difference in the immune reactivity of chimp and human lymphocytes appears to be related to the differential expression of Siglec-5. Taken together, these data may help explain human propensities for diseases associated with excessive activation of the adaptive immune system.
19558671 Oleic acid and peanut oil high in oleic acid reverse the inhibitory effect of insulin prod 2009 Jun 26 BACKGROUND: Chronic inflammation is a key player in pathogenesis. The inflammatory cytokine, tumor necrosis factor-alpha is a well known inflammatory protein, and has been a therapeutic target for the treatment of diseases such as Rheumatoid Arthritis and Crohn's Disease. Obesity is a well known risk factor for developing non-insulin dependent diabetes melitus. Adipose tissue has been shown to produce tumor necrosis factor-alpha, which has the ability to reduce insulin secretion and induce insulin resistance. Based on these observations, we sought to investigate the impact of unsaturated fatty acids such as oleic acid in the presence of TNF-alpha in terms of insulin production, the molecular mechanisms involved and the in vivo effect of a diet high in oleic acid on a mouse model of type II diabetes, KKAy. METHODS: The rat pancreatic beta cell line INS-1 was used as a cell biological model since it exhibits glucose dependent insulin secretion. Insulin production assessment was carried out using enzyme linked immunosorbent assay and cAMP quantification with competitive ELISA. Viability of TNF-alpha and oleic acid treated cells was evaluated using flow cytometry. PPAR-gamma translocation was assessed using a PPRE based ELISA system. In vivo studies were carried out on adult male KKAy mice and glucose levels were measured with a glucometer. RESULTS: Oleic acid and peanut oil high in oleic acid were able to enhance insulin production in INS-1. TNF-alpha inhibited insulin production but pre-treatment with oleic acid reversed this inhibitory effect. The viability status of INS-1 cells treated with TNF-alpha and oleic acid was not affected. Translocation of the peroxisome proliferator- activated receptor transcription factor to the nucleus was elevated in oleic acid treated cells. Finally, type II diabetic mice that were administered a high oleic acid diet derived from peanut oil, had decreased glucose levels compared to animals administered a high fat diet with no oleic acid. CONCLUSION: Oleic acid was found to be effective in reversing the inhibitory effect in insulin production of the inflammatory cytokine TNF-alpha. This finding is consistent with the reported therapeutic characteristics of other monounsaturated and polyunsaturated fatty acids. Furthermore, a diet high in oleic acid, which can be easily achieved through consumption of peanuts and olive oil, can have a beneficial effect in type II diabetes and ultimately reverse the negative effects of inflammatory cytokines observed in obesity and non insulin dependent diabetes mellitus.
19433411 The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseases. 2010 Apr OBJECTIVES: The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with type 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). METHODS: The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete. RESULTS: A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6 x 10(-4)), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02 x 10(-6)) in a total of 1577 patients with SLE and 4215 healthy individuals. CONCLUSION: A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases.
19370600 Single dose oral etoricoxib for acute postoperative pain in adults. 2009 Apr 15 BACKGROUND: Etoricoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor prescribed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis, and acute pain. The drug is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). A number of studies in acute postoperative pain have now been published. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single oral dose of etoricoxib for moderate to severe postoperative pain. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE, and the Oxford Pain Database, and reference lists of articles. Date of the most recent search: December 2008. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled clinical trials of single dose, oral etoricoxib for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion in the review and quality, and extracted data. The area under the pain relief versus time curve was used to derive the proportion of participants prescribed etoricoxib or placebo with at least 50% pain relief over six hours, using validated equations. Relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Information on use of rescue medication was used to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. Information on adverse effects was also collected. MAIN RESULTS: Five studies (880 participants) were included in the review. All five studies reported on 120 mg, with 655 participants in a comparison with placebo. At least 50% pain relief was reported by 64% with etoricoxib 120 mg and 10% with placebo (NNT 1.9 (1.7 to 2.1)). For dental studies only the NNT was 1.6 (1.5 to 1.8). Two studies also reported on higher doses of 180 and 240 mg, with 249 participants. At least 50% pain relief was reported by 79% with etoricoxib 120 mg and 12% with placebo (NNT 1.5 (1.3 to 1.7)).Significantly fewer participants used rescue medication when taking etoricoxib 120 mg than those taking placebo (NNT to prevent remedication 2.4 (2.1 to 2.9)), and the median time to use of rescue medication was 20 hours. Adverse events were reported at a similar rate to placebo, with no serious events. AUTHORS' CONCLUSIONS: Single dose oral etoricoxib produces high levels of good quality pain relief after surgery. The 120 mg dose is as effective as, or better than, other commonly used analgesics.
19268046 [Medin modular implant for total knee arthroplasty--mid-term results]. 2009 Feb PURPOSE OF THE STUDY To evaluate the mid-term results of total knee arthroplasty (TKA) using a Medin Modular joint prosthesis in a standard design preserving the posterior cruciate ligament. MATERIAL The study comprised 206 consecutive total knee arthroplasties, 10 bilateral, 60 in men and 136 in women. Twelve patients died of causes unrelated to the surgery and 14 knee replacements were lost to follow-up. A total of 180 were evaluated at an average follow-up of 6.5 years (range, 5 to 8.7 years). The patients ranged in age from 43 to 84 years (average, 69.5 years). The basic indication for surgery was osteoarthritis in 179 and rheumatoid arthritis in 37 cases. METHODS Pain, range of motion, stability and function were scored on a 100-point scale of the Hospital for Special Surgery (HSS) Scoring System. Subjective satisfaction was essessed by the patient's willingness to undergo the surgery again. At yearly intervals, radiographs in two projections were examined for radiolucent lines around the implant. The Kaplan-Meier survival curve was evaluated for the whole group and compared with that for non-infected cases only. The mechanical properties of the implant were most reliably shown by the survival curve for the subgroup of knee replacements free of infection. RESULTS At the final follow-up out of 180 knees, 169 were fully functioning and 11 required revision arthroplasty for the following reasons: polyethylene wear, one knee; instability, two; infection, six; patellar fracture, one; and problems associated with the femoro-patellar joint, one knee. The Kaplan-Meier curve for the whole group showed survival of 92 % of the implants at the end of the 9-years follow-up time. In the infection-free subgroup, in which aseptic loosenings were only included, there was a 95 % survival. The average range of flexion was over 106 degrees, and only 11 knees had flexion below 90 degree lack of. Extension from 5 to 10 degrees was found in four knees. Thirteen knees showed instability that did not interfere with function. In 191 knees, after surgery alignment was optimal, between 0 and 5-degree valgus; in 11 knees varus up to 5 degrees and valgus up to 10 degrees were found. No pain was recorded in 123 knees, occasional pain with no effect on function in 36 cases, and moderate pain after weight-bearing in 10 knees. By the HSS score, 136 knees had excellent and very good (over 90 points) outcomes and 21 had unsatisfactory or poor outcomes (below 85 points); the remaining 23 had satisfactory outcomes (between 89 and 85 points). The subjective evaluation was positive for 156 knees. Of 169 TKA evaluated radiographs, 141 were without signs of radiolucency, 17 showed a slight marginal radiolucent line and 11 had a more pronounced radiolucent line up to 1 mm in width, but without progression. DISCUSSION A total of 93 % of total replacements were evaluated and 7 % were lost to follow-up. Therefore, the number of remaining patients is big enough to make the group valid for assessment. The rate of complications, including 2.9 % of infected knees, is in agreement with the reported values. The occurence of polyethylene wear was negligible. A comparison of the cumulative survival curve for the whole group with that for the infection-free subgroup showed that the effect of infection on the TKA outcome was statistically significant (p=0.0431), and that late infection remains the most serious complication. Aseptic loosening plays a less important role in implant survival evaluated at mid-term intervals. CONCLUSIONS The rate of complications for Medin Modular implants evaluated at an average follow-up of 6.5 years is not different from the values reported for similar prostheses. The most serious complication is late infection. Persistent pain is usually located to the femoro-patellar articulation, but it seldom markedly affects joint function. The cumulative survival curve for the whole group was 92 % at a 9 years. The HSS evaluation of the whole group showed that 75 % of the knees achieved mor than 90 points.
21190368 Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids. 2011 Jan 27 The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC(50) values between 0.27 and 6.2 μM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyp's direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds.
20957046 The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. 2010 Oct 1 BACKGROUND: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases. METHODOLOGY/PRINCIPAL FINDINGS: During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist. We aimed to determine whether any biological activity of leflunomide could be attributed to a previously unappreciated interaction with the AhR. The currently established mechanism of action of leflunomide involves its metabolism to A771726, possibly by cytochrome P450 enzymes, followed by inhibition of de novo pyrimidine biosynthesis by A771726. Our results demonstrate that leflunomide, but not its metabolite A771726, caused nuclear translocation of AhR into the nucleus and increased expression of AhR-responsive reporter genes and endogenous AhR target genes in an AhR-dependent manner. In silico Molecular Docking studies employing AhR ligand binding domain revealed favorable binding energy for leflunomide, but not for A771726. Further, leflunomide, but not A771726, inhibited in vivo epimorphic regeneration in a zebrafish model of tissue regeneration in an AhR-dependent manner. However, suppression of lymphocyte proliferation by leflunomide or A771726 was not dependent on AhR. CONCLUSIONS: These data reveal that leflunomide, an anti-inflammatory drug, is an agonist of the AhR. Our findings link AhR activation by leflunomide to inhibition of fin regeneration in zebrafish. Identification of alternative AhR agonists is a critical step in evaluating the AhR as a therapeutic target for the treatment of immune disorders.
20393958 Single dose oral diflunisal for acute postoperative pain in adults. 2010 Apr 14 BACKGROUND: Diflunisal is a long-acting non-steroidal anti-inflammatory drug (NSAID) most commonly used to treat acute postoperative pain or chronic joint pain from osteoarthritis and rheumatoid arthritis. This review analyses the effectiveness and harm of different doses of diflunisal in the context of moderate to severe postoperative pain. OBJECTIVES: To assess efficacy, duration of action, and associated adverse events of single dose oral diflunisal in acute postoperative pain in adults. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2010. SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials of single dose orally administered diflunisal in adults with moderate to severe acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. MAIN RESULTS: Nine studies in dental, orthopedic and gynaecological surgery met the inclusion criteria, testing doses of diflunisal from 125 mg to 1000 mg.For diflunisal 1000 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.1 (1.8 to 2.6) (6 studies, 391 participants); the NNT to prevent remedication within 6 hours was 1.9 (1.7 to 2.3), and within 12 hours was 2.2 (1.9 to 2.7) (6 studies, 409 participants). More participants experienced adverse events with diflunisal 100 mg than with placebo, but none were serious or led to withdrawal.For diflunisal 500 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.6 (2.1 to 3.3) (6 studies, 357 participants); the NNT to prevent remedication within 6 hours was 2.6 (2.1 to 3.4) (6 studies, 390 participants), and within 12 hours was 2.9 (2.3 to 4.0) (5 studies, 329 participants). Adverse events did not differ significantly from placebo. AUTHORS' CONCLUSIONS: Diflunisal has an analgesic effect similar to other NSAIDs in single dose, but benefits from providing significant analgesia for about twelve hours. This property may be useful when regular dosing is needed, or when taking several doses of a shorter acting analgesic is impractical.
19866334 Antitumor necrotic factor agent promotes BMP-2-induced ectopic bone formation. 2010 Mar Etanercept (ETN), which is a recombinant human soluble tumor necrosis factor (TNF) receptor that inhibits TNF activity, is effective in the treatment of rheumatoid arthritis. We investigated the effect of ETN on recombinant human bone morphogenetic protein-2 (rhBMP-2)-induced ectopic bone formation in vivo. A block copolymer composed of poly-D,L-lactic acid with random insertion of p-dioxanone and polyethylene glycol (PLA-DX-PEG polymer) was used as the delivery system. Polymer discs (6 mm, 30 mg) containing 5 microg rhBMP-2 were implanted into the left dorsal muscle pouch of mice (n = 50). In the systemic administration groups (n = 5 per group), ETN was subcutaneously injected (25 mg/human = 12.5 microg/mouse) twice per week in a dose-dependent manner (placebo, 12.5 x 10(-3), 12.5 x 10(-1), 12.5, 125 microg), whereas a single dose of ETN (placebo, 12.5 x 10(-3), 12.5 x 10(-1), 12.5, 125 microg) was embedded in each rhBMP-2 polymer disc in the local administration groups (n = 5 per group). Three weeks after implantation, the mice were killed and the implants were analyzed. Implants in the optimally dosed groups had increased radiodensity, which was consistent with a significant increase in bone mineral content of the ossicles. Bone histomorphology revealed a significant increase in bone volume/total volume, number of osteoblasts, osteoblast surface/bone surface, and a significant decrease in the number of osteoclasts, osteoclast surface/bone surface in the optimal dosed systemic and locally administered groups. These data suggest that the optimal dose of ETN, administered either systemically or locally, enhanced the bone-inducing capacity of BMP with no apparent adverse systemic effects.
19781326 Value of the peripheral blood B-cells subsets in patients with ankylosing spondylitis. 2009 Aug 5 BACKGROUND: The role of B-cell remains an enigma in the pathogenesis of ankylosing spondylitis (AS). This study aimed to investigate the distributions of B-cells and subsets in peripheral blood of AS patients and observe their changes in etanercept-treated AS patents. METHODS: We detected the proportions of CD19(+) B-cell, naive B-cell (CD19(+)CD27-), memory B-cell (CD19(+)CD27dim) and plasmablast (CD19(+)CD27high) in peripheral blood of 66 patients with AS (39 at active stage, 27 at stable stage; 35 patients with peripheral joint involvement, 31 patients with axial involvement alone), 30 patients with rheumatoid arthritis (RA) and 30 healthy volunteers using flow cytometry. And then we observed the changes of the above indexes of 39 active AS patients treated with etanercept in a randomized, double-blind, placebo-controlled trial. RESULTS: (1) Percentages of CD19(+) B-cells in active or peripheral joint involvement AS patients increased more obviously than those in stable or axial involvement alone AS patients (both P = 0.001), and percentage of CD19(+)CD27high B-cells in AS patients with peripheral joint involvement was significantly higher than that in cases with axial involvement alone or healthy volunteers (P = 0.005 and 0.006, respectively); (2) The percentage of CD19(+) B-cells in AS patients was positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, Patient's Global Assessment (PGA) scores, total back pain scores and nocturnal back pain scores (r = 0.270, 0.255, 0.251 and 0.266, P = 0.029, 0.039, 0.042 and 0.031, respectively); (3) At week 6 and week 12, there were no statistical differences of the percentages of B-cells and subsets between etanercept group and placebo group of AS patients (P > 0.05); the percentage of CD19(+) B-cells in etanercept group was higher than that in healthy volunteers at week 12 (t = 3.320, P = 0.003). CONCLUSIONS: Misbalance is present in B-cells and some subsets in peripheral blood of active AS patients with peripheral joint involved. B-cells might play an important role in the pathogenesis of AS patients. The high percentage of CD19(+) B-cells in active AS patients cannot be down-regulated after 12-week etanercept treatment.
19588426 Single dose oral etodolac for acute postoperative pain in adults. 2009 Jul 8 BACKGROUND: Etodolac is a selective cyclo-oxygenase-2 (COX-2) inhibitor, with evidence of efficacy in osteoarthritis and rheumatoid arthritis. Its analgesic efficacy in postoperative pain has not been clearly established. There are no systematic reviews on Etodolac's use in this condition. OBJECTIVES: To assess the analgesic efficacy of etodolac in single oral doses for moderate and severe postoperative pain. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009. SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials of single dose orally administered etodolac (any formulation) in adults with moderate to severe acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. MAIN RESULTS: Nine studies (1459 participants) compared etodolac and placebo. Studies were of adequate reporting quality, and the majority of participants had pain following dental extractions. The dose of etodolac used was 25 mg to 1200 mg, with most of the information for 100 mg and 200 mg. For at least 50% pain relief over 4 to 6 hours compared with placebo the NNT for etodolac 100 mg (498 participants) was 4.8 (3.5 to 7.8) and for etodolac 200 mg (670 participants) it was 3.3 (2.7 to 4.2). Very limited information with the extended release formulation did not suggest improved benefit for this outcome.The proportion of participants with at least 50% pain relief was 41% with 100 mg and 44% with 200 mg. Remedication was needed by about 60% with etodolac 200 mg or 400 mg over 6 to 8 hours, compared with almost 80% with placebo.Adverse events were uncommon, and not significantly different form placebo. AUTHORS' CONCLUSIONS: Etodolac 200 mg may be a useful analgesic in postoperative pain, with efficacy similar to paracetamol 1000 mg and celecoxib 200 mg. Higher doses may provide analgesia equivalent to more commonly used drugs, such as ibuprofen 400 mg, naproxen 500 mg and diclofenac 50 mg.
19462990 Pattern recognition analysis for the prediction of adverse effects by nonsteroidal anti-in 2009 Jun 15 Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat rheumatoid arthritis, osteoarthritis, acute pain, and fever. However, NSAIDs have side effects that include gastric erosions, ulceration, bleeding, and perforation, etc. Selective cyclooxygenase (COX)-2 inhibitors have been developed to avoid the adverse drug reaction of traditional NSAIDs. The COX-2 inhibitors have a different mechanism of action from nonselective COX inhibitors. In this study, pattern recognition analysis of the (1)H nuclear magnetic resonance (NMR) spectra of urine was performed to develop surrogate biomarkers related to the gastrointestinal (GI) damage induced by NSAIDs in rats. Urine was collected for 5 h after administering the following NSAIDs at high doses: celecoxib (133 mg kg(-1), p.o.), a COX-2-selective inhibitor; and indomethacin (25 mg kg(-1), p.o.) or ibuprofen (800 mg kg(-1), p.o.), nonselective COX inhibitors. The urine was analyzed using 600 M (1)H NMR for spectral binning and targeted profiling. The level of gastric damage in each animal was also determined. Indomethacin and ibuprofen caused severe gastric damage, but no lesions were observed in the celecoxib-treated rats. The (1)H NMR urine spectra were divided into spectral bins (0.04 ppm) for global profiling, and 36 endogenous metabolites were assigned for targeted profiling. Multivariate data analyses were carried out to recognize the spectral pattern of endogenous metabolites related to NSAIDs using partial least-squares discrimination analysis (PLS-DA). There were different clusterings of (1)H NMR spectra according to the gastric damage scores in global profiling. In targeted profiling, a few endogenous metabolites of allantoin, taurine, and dimethylamine were selected as putative biomarkers for the gastric damage induced by NSAIDs. The results of global and targeted profilings suggest that the gastric damage induced by NSAIDs can be screened in the preclinical stage of drug development using a current metabolomics study. In addition, the putative biomarkers might also be useful for predicting the risk of adverse effects caused by NSAIDs.
19350211 Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity 2009 Dec B cells are critical players in the orchestration of properly regulated immune responses, providing protection against infectious agents without inflicting autoinflammatory damage. A balanced B cell compartment is also essential to create protective immunity in response to vaccines. This difficult compromise is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to powerfully modulate other components of the innate and adaptive immune system. For the most part, however, the necessary division of labor among different B cell populations is poorly understood. B cell dysfunction has been implicated in multiple autoimmune conditions. The physiological importance and complexity of B cell functions has been brought to the fore in recent years by the success of rituximab-based B cell depletion therapy (BCDT) in multiple autoimmune diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS) which are conventionally viewed as T-cell mediated conditions. Given the widespread utilization of BCDT in malignant and autoimmune diseases and the key role of B cells in both protective immunity and pathogenic autoimmunity, a better understanding of B cell functions is of the essence and a focus of the research in our division. We are investigating these issues through a variety of approaches, including the study of the phenotype and function of human B cell populations in health, their perturbation in autoimmune disease states, the effects of targeted biologic therapies, and the study of relevant murine models.
23637669 Accuracy and reliability of MRI quantitative measurements to assess spinal cord compressio 2010 Aug STUDY TYPE:  Reliability study Introduction:  Cervical spondylotic myelopathy (CSM) is the most common spinal cord disorder in persons more than 55 years old. Despite multiple neuroimaging approaches proposed to quantify the spinal cord compromise in CSM patients, magnetic resonance imaging (MRI) remains the procedure of choice by providing helpful information for clinical decision making, determining optimal subpopulations for treatment, and selecting the optimal treatment strategies. However, the validity, reliability, and accuracy of the MRI quantitative measurements have not yet been addressed. OBJECTIVE:  To assess the intra- and inter-observer reliability of MRI quantitative measurements of the spinal cord compromise in CSM patients. METHODS:  Seventeen CSM patients (13 male) of mean age 54.5 years old were selected from the AOSpine North America database. The patients had different combinations of stenotic levels (1-4 levels) and the clinical severity (range mJOA baseline: 8-18). Asymptomatic or previous surgically treated CSM, active infection, neoplastic disease, rheumatoid arthritis, ankylosing spondylitis, trauma, or concomitant lumbar stenosis were excluded. The patients underwent preoperative MRI using 1.5T (15 patients) and 3T (two patients) scanner, including mid-sagittal T1-weighted, axial and mid-sagittal T2-weighted series. MRI data were analyzed (Mango 2.0 software; Multi-Image Analysis GUI) by four blind raters in three different sessions. Four measurements were analysed: transverse area (TA) (Figure 1), compression ratio (CR) (Figure 2), maximal canal compromise (MCC), and maximal spinal cord compression (MSCC) (Figure 3). The differences for each measurement were evaluated using mixed-effect ANOVA models (ratter, session, ratter x session). The intra- and inter-rater reliability was evaluated with intraclass correlation coefficients (ICC) (Figure 4). Figure 1 Transverse area (TA)Figure 2 Compression ratio (CR = AP/W)Figure 3 Maximal canal compromise (MCC), and maximal spinal cord compression (MSCC). MCC(%) = 1-[Dx/(Da+Db)/2] × 100%; MSCC(%) = 1-[dx/(da+db)/2] × 100%Figure 4 Intraclass correlation coefficients (ICC) Results:  The principal findings were: (i) for TA (71.48 ± 12.99mm2), the intra-rater agreement was 0.97 (95% CI, range 0.94-0.99) and the inter-rater agreement was 0.76 (95% CI, range 0.49-0.90); (ii) for CR (0.35 ± 0.04%), 0.94 (95% CI, range 0.88-0.98), and 0.79 (95% CI, range 0.57-0.91) respectively; (iii) for MCC (83.21 ± 2.08%), 0.95 (95% CI, range 0.89-0.98), and 0.64 (95% CI, range 0.28-0.85) respectively; and (iv) for MSCC (82.87 ± 1.52%), 0.93 (95% CI, range 0.86-0.97), and 0.84 (95% CI, range 0.65-0.93) respectively. CONCLUSIONS:  Our data suggest that three out of four measurements (TA, CR and MSCC) have acceptable intra- and interreliability coefficients (ICC > 0.75). However, for the maximal canal compromise measure, although the intrareliability was acceptable, the inter-rater reliability was not acceptable (0.64). Based on this study, we recommend that three MRI measures: transverse area, compression ratio and maximal spinal cord compression should be used in the imaging assessment of the spinal cord in CSM patients.