Rheumatoid Arthritis: Calgary

Hirota SA, Beck PL, MacDonald JA. · Smooth Muscle Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada. · Recent Pat Inflamm Allergy Drug Discov. · Pubmed #19149741 No free full text.

Abstract: 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.

Stinton LM, Fritzler MJ. · Department of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1. · Autoimmun Rev. · Pubmed #17967730 No free full text.

Abstract: Musculoskeletal (MSK) disorders constitute one of the most common clinical presentations to clinical care givers. Within this category of illnesses, systemic autoimmune rheumatic diseases (SARD) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SjS) and rheumatoid arthritis (RA) are included in the differential diagnosis. A hallmark of SARD is the production of autoantibodies, which are routinely requested as a guide to diagnosis and clinical decision making. The field of serological tests, including the detection of autoantibodies, is complex and often leads to confusion and misunderstanding. When used appropriately, autoantibodies can be a valuable adjunct to the diagnosis, and occasionally therapy and prognosis, of SARD. The role of autoantibody testing and a 'practical' approach to using these tests is the focus of this paper.

Jones JL, Loftus EV. · Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada. · Inflamm Bowel Dis. · Pubmed #17600819 links to  free full text

Abstract: With the increasingly widespread use of immunosuppressive and biologic agents for the treatment of Crohn's disease and ulcerative colitis come concerns about potential long-term consequences of such therapies. Disentangling the potential confounding effects of the underlying disease, its extent, severity, duration, and behavior, and concomitant medical therapy has proven to be exceedingly difficult. Unlike the case in rheumatoid arthritis, the overwhelming preponderance of population-based evidence suggests that a diagnosis of inflammatory bowel disease (IBD) is not associated with an increased relative risk of lymphoma. However, well-designed studies that evaluate the potential modifying effect of IBD severity have yet to be performed. Although the results from hospital- and population-based studies have conflicted, the results of a recent meta-analysis suggest that patients receiving purine analogs for the treatment of IBD have a lymphoma risk approximately 4-fold higher than expected. Analyses of lymphoma risk in patients receiving biologic agents directed against tumor necrosis factor-alpha are confounded by concomitant use of immunosuppressive agents in most of these patients. Nevertheless, there may be a small but real risk of lymphoma associated with these therapies. Although the relative risk of lymphoma may be elevated in association with some of the medical therapies used in the treatment of IBD, this absolute risk is low. Weighing the potential risk of lymphoma associated with select medical therapies against the risk of undertreating IBD will help physicians and patients to make more informed decisions pertaining to the medical management of IBD.

Giembycz MA, Smith SJ. · Department of Pharmacology and Therapeutics, Respiratory Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. · Curr Pharm Des. · Pubmed #17020529 No free full text.

Abstract: Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.

Ajuebor MN, Carey JA, Swain MG. · Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada. · J Immunol. · Pubmed #16887960 links to  free full text

Abstract: The chemokine receptor CCR5 came into worldwide prominence a decade ago when it was identified as one of the major coreceptors for HIV infectivity. However, subsequent studies suggested an important modulatory role for CCR5 in the inflammatory response. Specifically, CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Moreover, T cell-mediated immune responses are proposed to be critical in the pathogenesis of autoimmune and viral liver diseases, and recent clinical and experimental studies have also implicated CCR5 in the pathogenesis of autoimmune and viral liver diseases. Therefore, in this brief review, we highlight the evidence that supports an important role of CCR5 in the pathophysiology of T cell-mediated liver diseases with specific emphasis on autoimmune and viral liver diseases.

Norman MU, Hickey MJ. · Immunology Research Group, University of Calgary, Calgary, AB, Canada. · Tissue Antigens. · Pubmed #16101827 No free full text.

Abstract: The recruitment of leukocytes to inflamed tissues plays an essential role in combating infection and promoting wound healing. However, in autoimmune diseases such as multiple sclerosis and diabetes, leukocytes enter tissues and contribute to inappropriate inflammatory responses, which cause tissue injury and dysfunction. In diseases of this type, lymphocytes play critical roles in initiating and maintaining these aberrant inflammatory responses. The aim of this review is to examine the mechanisms whereby T-lymphocytes enter tissues in autoimmune diseases and to compare these mechanisms between various organs and diseases. An overview of the mechanisms of leukocyte recruitment and the techniques used to study leukocyte trafficking is provided, focusing on the use of intravital microscopy as a tool to assess the functional microvasculature in vivo. We also discuss the series of tissue homing events which allow naïve lymphocytes to first enter lymph nodes and undergo activation, then subsequently to home to the peripheral organ where their cognate antigen is present. Finally, we examine mechanisms of leukocyte recruitment in diseases such as multiple sclerosis, autoimmune diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and asthma.

Ting PT, Barankin B. · University of Calgary, Alberta. · Can Fam Physician. · Pubmed #15732219 links to  free full text

This publication has no abstract.

Barr SG, Martin L, Chung C, Maksymowych WP. · Department of Medicine, University of Calgary, Canada. · Clin Exp Rheumatol. · Pubmed #15552513 No free full text.

Abstract: Regulatory authorities in Canada have expressed a vital need for pharmacoepidemiological data on long-term effectiveness, safety, and cost-benefit of new therapies, particularly in comparison to currently available therapies, in routine clinical practice to allow informed decision making in listing new therapies on formulary. We describe the evolution of a new model of pharmacosurveillance involving a partnership between academic and community rheumatologists, government, and industry whereby access to therapy is conditional on participation in an industry-funded pharmacosurveillance study that assesses long-term effectiveness, safety, and cost-benefit. Though funded by industry, the program is administered by government and designed and operated at arms length from industry. The clinic data sheets are available at www. altarheum.com. The program also provides a sustainable model for promoting observational research on therapeutics in general.

Hart DA, Kydd AS, Frank CB, Hildebrand KA. · Department of Surgery, McCaig Centre for Joint Injury and Arthritis Research, University of Calagary, 3330 Hospital Drive NW, Calgary, Alta., Canada T2N 4N1. · Best Pract Res Clin Rheumatol. · Pubmed #15121039 No free full text.

Abstract: Rheumatoid arthritis (RA) is a systemic inflammatory disease that can elicit a variable disease course, can influence a variable number of joints, and can exhibit a variable response to treatment. All of these factors contribute to the degree and extent of damage to joint components, as well as the potential for repair of other injured joint tissues/components. Furthermore, some of the RA treatments/drugs themselves can influence repair and injury responses, as well as the outcome of surgical interventions for advanced disease. However, as treatments and interventions become more sophisticated and successful in patient populations, the opportunity to initiate the repair/replacement of the damaged joint tissues also becomes more of a reality. This review will address the current clinical findings in the literature, and then discuss the issues and opportunities to initiate repair of damaged or injured joint tissues in order to restore joint function. These include growth factors, gene therapy, and bioengineered tissues, alone or in combination to augment endogenous repair or replace tissue damaged beyond such repair capabilities.

Rankin JA. · University of Calgary, Faculty of Nursing, Calgary, Alberta, Canada. · AACN Clin Issues. · Pubmed #14767362 No free full text.

Abstract: Inflammation may be defined as the normal response of living tissue to injury or infection. It is important to emphasize two components of this definition. First, that inflammation is a normal response and, as such, is expected to occur when tissue is damaged. Indeed, if injured tissue did not exhibit signs of inflammation this would be considered abnormal. Secondly, inflammation occurs in living tissue, hence the need for an adequate blood supply to the tissues in order for an inflammatory response to be exhibited.The inflammatory response may be triggered by mechanical injury, chemical toxins, invasion by microorganisms, and hypersensitivity reactions. Three major events occur during the inflammatory response: the blood supply to the affected area is increased substantially, capillary permeability is increased, and leucocytes migrate from the capillary vessels into the surrounding interstitial spaces to the site of inflammation or injury.The inflammatory response represents a complex biological and biochemical process involving cells of the immune system and a plethora of biological mediators. Cell-to-cell communication molecules known collectively as cytokines play an extremely important role in mediating the process of inflammation. An extensive exposition of this complex phenomenon is beyond the scope of this article. Rather, the author provides a review of inflammation, an overview of the role of certain biological mediators in inflammation, and a discussion of the implications of certain biological response modifiers in clinical practice.

Krein PM, Winston BW. · Immunology Research Group, University of Calgary, Calgary, AB, Canada. · Chest. · Pubmed #12475802 links to  free full text

Abstract: Idiopathic pulmonary fibrosis (IPF) is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor (TGF)-beta, insulin-like growth factor (IGF)-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis (scleroderma). We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in fibrotic lung diseases and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with IPF.

Ajuebor MN, Swain MG, Perretti M. · Liver Unit, Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada T2N 4N1. · Biochem Pharmacol. · Pubmed #11960595 No free full text.

Abstract: Chemokines and their receptors are a large family of inflammatory molecules responsible for a number of biological functions, including the accumulation of leukocytes at tissue sites. Over the past 10 years, a number of studies have indicated a role for chemokines and chemokine receptors in the pathophysiology of several inflammatory diseases, examples of which are multiple sclerosis, atherosclerosis, rheumatoid arthritis, and gastrointestinal diseases including hepatic disease. For this reason, it is not surprising that modulation of their pharmacology could be a prime target for drug discovery. This commentary provides a brief synopsis of our current knowledge of the role of chemokines and their receptors in the inflammatory process, and highlights the pros and possibly cons of chemokine and chemokine receptor antagonism in the therapeutic approach to several inflammatory diseases.

Edworthy S, Zummer M, Garner S, Boire G, Leclercq S, Bykerk V, Kraag G, Markland J, Thomas D, Thomson J, Henderson J. · University of Calgary, Calgary, Alberta, Canada. · J Rheumatol. · Pubmed #18597407 No free full text.

Abstract: OBJECTIVE: To investigate rheumatology practice in Canada with regard to evaluating disease activity status and treatment regimens in patients with rheumatoid arthritis (RA). It was hypothesized that patients with "smoldering" disease activity were not being adequately treated. METHODS: Rheumatologists were invited to participate by the Canadian Rheumatology Association in an audit entitled the Assessment in Rheumatology (AIR) program. From across Canada, 65 rheumatologists participated. One thousand five hundred ninety-six consecutive patients with RA seen in regular clinics were classified according to 4 states of disease activity: remission, controlled adequately, smoldering, and uncontrolled. Demographics (age, sex, geographic region), therapy (nonsteroidal antiinflammatory drugs, disease modifying antirheumatic drugs, biologicals, steroids), joint counts (tender/swollen), comorbidity, and treatment decisions at the time of the visit were recorded. Data were collected at the time of the visit with personal digital assistants (PDA) and aggregated, without personal identifiers, for analysis in SPSS. RESULTS: The majority of patients had "smoldering" (29%) or "uncontrolled" disease (23%), with the remainder in "remission" (15%) or "controlled adequately" (33%) at the time of their visit. Following the appointment, the uncontrolled group had a 100% increase (from 10.4% to 23.4%) in the addition of biological agents; however, there was no significant increase in the rates for those with smoldering disease (19.4% to 20.5%). CONCLUSION: Despite Canada's universal healthcare system, current treatment regimens may not be optimized on the basis of disease activity. A large proportion of patients with RA (29%) seen in Canadian rheumatology practices may be experiencing unnecessary disease for a variety of reasons.

De Coster C, Fitzgerald A, Cepoiu M, Anonymous00013. · Health Outcomes, Calgary Health Region, Calgary, Alberta, Canada. · Clin Rheumatol. · Pubmed #18560920 No free full text.

Abstract: As part of a larger body of work to develop a rheumatology priority referral score, a literature review was conducted. The objective of the literature review was to identify preexisting priority-setting, triage, and referral tools/scales developed to guide referrals from primary care to specialist care/consultation usually provided by a rheumatologist. Using a combination of database, citation, Internet, and hand-searching, 20 papers were identified that related to referral prioritization in three areas: rheumatoid arthritis (RA; 5), musculoskeletal (MSK) diseases other than RA (3), and MSK diseases in general (12). No single set of priority-setting criteria was identified for rheumatologic disorders across the spectrum of patients who may be referred from primary care providers (PCPs) to rheumatologists. There appears to be more congruence on conditions at either end of the urgency spectrum with conditions such as suspected cranial arteritis or systemic vasculitis deemed to be emergency referrals and fibromyalgia and other soft-tissue syndromes deemed to be more routine referrals. Between these two extremes, there is a divergence of opinion about urgency and few papers on the issue. The exception to this is referral for early RA for which several criteria have been established. Despite the inherent complexities in developing a tool to prioritize patients referred by PCPs to rheumatologists, there are compelling reasons to proceed. With the aging of the population, the number of patients being referred to rheumatologists is expected to increase. With pharmaceutical advances, there are demonstrable benefits in early referral for some conditions. These trends have led to increased pressure on scarce rheumatological human resources. A tool to prioritize referrals is a critical component of improving access and the referral process.

Bhanji RA, Eystathioy T, Chan EK, Bloch DB, Fritzler MJ. · Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Canada. · Clin Immunol. · Pubmed #17870671 links to  free full text

Abstract: GW bodies (GWBs) are unique cytoplasmic structures involved in messenger RNA (mRNA) processing and RNA interference (RNAi). GWBs contain mRNA, components of the RNA-induced silencing complex (RISC), microRNA (miRNA), Argonaute proteins, the Ge-1/Hedls protein and other enzymes involving mRNA degradation. The objective of this study was to identify the target GWB autoantigens reactive with 55 sera from patients with anti-GWB autoantibodies and to identify clinical features associated with these antibodies. Analysis by addressable laser bead immunoassay (ALBIA) and immunoprecipitation of recombinant proteins indicated that autoantibodies in this cohort of anti-GWB sera were directed against Ge-1/Hedls (58%), GW182 (40%) and Ago2 (16%). GWB autoantibodies targeted epitopes that included the N-terminus of Ago2 and the nuclear localization signal (NLS) containing region of Ge-1/Hedls. Clinical data were available on 42 patients of which 39 were female and the mean age was 61 years. The most common clinical presentations were neurological symptoms (i.e. ataxia, motor and sensory neuropathy) (33%), Sjögren's syndrome (SjS) (31%) and the remainder had a variety of other diagnoses that included systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary biliary cirrhosis (PBC). Moreover, 44% of patients with anti-GWB antibodies had reactivity to Ro52. These studies indicate that Ge-1 is a common target of anti-GWB sera and the majority of patients in a GWB cohort had SjS and neurological disease.

Weljie AM, Dowlatabadi R, Miller BJ, Vogel HJ, Jirik FR. · Metabolomics Research Centre, Department of Biological Sciences, Department of Biochemistry and Molecular Biology, and the McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada. · J Proteome Res. · Pubmed #17696462 No free full text.

Abstract: Rheumatoid arthritis, a debilitating, systemic inflammatory joint disease, is likely accompanied by alterations in circulating metabolites. Here, an 1H NMR spectroscopy-based metabolomics approach was developed to establish a metabolic 'biomarker pattern' in a model of rheumatoid arthritis, the K/BxN transgenic mouse. Sera obtained from arthritic K/BxN mice (N = 15) and a control population (N = 19) having the same genetic background, but lacking the arthritogenic T-cell receptor KRN transgene, were compared by 1H NMR spectroscopy. A unique method was developed by combining technologies such as ultrafiltration to remove proteins from serum samples, quantitative 'targeted profiling' of known metabolites, pseudo-quantitative profiling of unknown resonances, a supervised O-PLS-DA pattern recognition analysis, and a metabolic-pathway based network analysis for interpretation of results. In total, 88 spectral features were profiled (59 metabolites and 28 unknown resonances). A highly significant subset of 18 spectral features (15 known compounds and 3 unknown resonances) was identified (p = 0.00075 using MANOVA) that we term a 'metabolic bioprofile'. We identified metabolites relating to nucleic acid, amino acid, and fatty acid metabolism, as well as lipolysis, reactive oxygen species generation, and methylation. Pathway analysis suggested a shift from metabolites involved in numerous reactions (hub-metabolites) toward intermediates and metabolic endpoints associated with arthritis. The results attest to the metabolic complexity of systemic inflammation and to the power of the experimental approach for identifying a wide variety of disease-associated marker candidates. The diagnostic and prognostic implications of monitoring a spectrum of metabolic events simultaneously using serum samples is discussed with respect to the potential for individualized medicine.

Suchowersky O, Muthipeedika J. · Movement Disorders Program, Department of Clinical Neurosciences, University of Calgary/Calgary Health Region, Calgary, Alberta, Canada. · Nat Clin Pract Neurol. · Pubmed #16932507 No free full text.

Abstract: Background A 75-year-old woman with rheumatoid arthritis presented with a 4-year history of chorea to a hospital movement disorder clinic. The involuntary movements were initially mild, affecting only the right side of the body, but gradually worsened and became bilateral. There was no relevant family history. Medications included hormone replacement therapy (HRT), diclofenac sodium, vitamin D, folic acid, methotrexate and zopiclone. On examination, bilateral choreiform movements were seen, affecting the face and limbs, with the right side more severely affected than the left.Investigations Neuropsychological testing, laboratory blood and DNA testing, echocardiogram, MRI of the brain, and brain perfusion single-photon emission computed tomography (SPECT) scanning.Diagnosis HRT-related chorea, possibly caused by a predisposition secondary to rheumatoid arthritis and small-vessel ischemic disease, or subclinical childhood rheumatic fever.Management Discontinuation of HRT.

Patten SB, Williams JV, Wang J. · Department of Community Health Sciences, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. · BMC Musculoskelet Disord. · Pubmed #16638139 links to  free full text

Abstract: BACKGROUND: Studies using clinical and volunteer samples have reported an elevated prevalence of mood disorders in association with rheumatoid arthritis and osteoarthritis. Clinical studies using anxiety rating scales have reported inconsistent results, but studies using diagnostic instruments have reported that anxiety disorders may be even more strongly associated with arthritis than is depression. One study reported an association between lifetime substance use disorders and arthritis. METHODS: Data from iteration 1.2 of the Canadian Community Health Survey (CCHS) were used. This was a large-scale national Canadian health survey which administered the World Mental Health Composite International Diagnostic Interview to a sample of 36,984 subjects randomly selected from the national population. In the CCHS 1.2, subjects were asked whether they had been diagnosed by a health professional with arthritis or rheumatism. RESULTS: Subjects reporting arthritis or rheumatism had an elevated prevalence of mood, anxiety and substance use disorders. The strength of association resembled that seen in an omnibus category reporting any chronic condition, but was weaker than that seen with back pain or fibromyalgia. The effect of arthritis or rheumatism interacted with age, such that the odds ratios became smaller with increasing age. Mood and anxiety disorders, along with arthritis or rheumatism made an independent contribution to disability. CONCLUSION: Arthritis is associated with psychiatric morbidity in the general population, and this morbidity is seen across a variety of mental disorders. The strength of association is consistent with that seen in persons with other self-reported medical conditions.

Jarand J, Zochodne DW, Martin LO, Voll C. · Department of Medicine, University of Calgary, Calgary, Alberta T2N 4NI. · J Rheumatol. · Pubmed #16511935 No free full text.

Abstract: The use of anti-tumor necrosis factor-a (TNF-a) therapies has led to improved outcomes in the treatment of rheumatoid arthritis (RA). However, the use of these new therapeutic agents requires careful monitoring for adverse effects. We describe 3 patients who developed neurological disease closely associated with the use of infliximab, a monoclonal antibody that binds to and inactivates TNF-a. All had evidence of polyneuropathy, demyelinating in one and axonal in 2. One patient had a central nervous system syndrome. Physicians should be aware of these potential adverse effects when treating patients with infliximab.

Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW. · Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. · J Immunol. · Pubmed #16339568 links to  free full text

Abstract: Macrophages are activated during an inflammatory response and produce multiple inflammatory cytokines. IL-18 is one of the most important innate cytokines produced from macrophages in the early stages of the inflammatory immune response. Monocyte chemoattractant protein (MCP-1) is expressed in many inflammatory diseases such as multiple sclerosis and rheumatoid arthritis, and its expression is correlated with the severity of the disease. Both IL-18 and MCP-1 have been shown to be involved in inflammatory immune responses. However, it has been unclear whether IL-18 is involved in the induction of MCP-1. This investigation was initiated to determine whether IL-18 can induce MCP-1 production, and if so, by which signal transduction pathways. We found that IL-18 induced the production of MCP-1 in macrophages, which was IL-12-independent and was not mediated by autocrine cytokines such as IFN-gamma or TNF-alpha. We then examined signal transduction pathways involved in IL-18-induced MCP-1 production. We found that IL-18 did not activate the IkappaB kinase/NF-kappaB pathway, evidenced by no degradation of IkappaBalpha and no translocation of NF-kappaB p65 to the nucleus in IL-18-stimulated macrophages. Instead, IL-18 activated the PI3K/Akt and MEK/ERK1/2 pathways. Inhibition of either of these pathways attenuated MCP-1 production in macrophages, and inhibition of both signaling pathways resulted in the complete inhibition of MCP-1 production. On the basis of these observations, we conclude that IL-18 induces MCP-1 production through the PI3K/Akt and MEK/ERK1/2 pathways in macrophages.

Westaway MD, Hu WY, Stratford PW, Maitland ME. · Faculty of Kinesiology, University of Calgary, 19 Discovery Valley Cove SW, Calgary, Alb., Canada T3H 5H3. · Man Ther. · Pubmed #16038857 No free full text.

Abstract: An investigation of intra- and inter-rater reliability anterior atlantodental interval (AADI) measurements was conducted using flexion/extension plain radiographs. Flexion and extension lateral radiographs of individuals investigated for atlantoaxial instability were measured for AADI on three occasions. Intra-rater intraclass correlation coefficients (ICC) were calculated for both flexion (0.99) and extension (0.96). Inter-rater ICCs were 0.93 and 0.84 for flexion and extension, respectively. The AADI measurement proved to be reproducible with a minimal standard of error, between and within raters.

Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello CA. · University of Calgary, Calgary, Alberta, Canada. · Arthritis Rheum. · Pubmed #15934079 links to  free full text

Abstract: OBJECTIVE: To assess the efficacy of anakinra treatment in patients with adult-onset Still's disease (AOSD) that is refractory to corticosteroids, methotrexate (MTX), and etanercept. METHODS: Four patients with AOSD were treated with prednisone and MTX and 2 patients were also treated with etanercept for worsening symptoms and indicators of systemic inflammation. White blood cells (WBCs), C-reactive protein (CRP) levels and/or erythrocyte sedimentation rate, and ferritin levels were measured and, in 1 patient, serum creatinine levels were determined. Treatment with anakinra at 100 mg/day was initiated. RESULTS: The index patient's disease was refractory to treatment with prednisone (30 mg/day) and MTX, with spiking fevers, rash, synovitis, a serum ferritin level of 8,400 ng/ml (normal </=200), and a CRP level of 86 mg/liter (normal <8). Levels of interleukin-1beta (IL-1beta), IL-1alpha, IL-6, IL-1 receptor antagonist, and IL-18 were elevated. Just prior to anakinra treatment, the WBC count was 14,600/mm(3), the CRP level was 86 mg/liter, and the ferritin level was 573 ng/ml, with daily spiking fevers to 104 degrees F, rash, and swollen joints. Within hours of the first injection, the patient was afebrile and asymptomatic; within days, the WBC count, ferritin level, and CRP level decreased into the normal range. On 2 occasions, anakinra was withheld. Within a few days, the WBC count rose to >20,000/mm(3) with prominent neutrophilia, the CRP level rose to >200 mg/liter, and the ferritin level rose to >3,000 ng/ml. Upon restarting anakinra, the patient became afebrile, the WBC count fell to 8,000/mm(3), the CRP level fell to <3 mg/liter, and the ferritin level fell to <300 ng/ml. Three additional patients with refractory AOSD who experienced rapid reductions in fever, symptoms, and markers of inflammation when treated with anakinra are reported. CONCLUSION: Refractory AOSD appears to be IL-1-mediated since anakinra decreases hematologic, biochemical, and cytokine markers and also produces rapid reductions in systemic and local inflammation. Reported efficacy of tumor necrosis factor-blocking therapies in AOSD may be due to a reduction in IL-1.

Oberle K, Allen MN. · Faculty of Nursing, University of Calgary. · West J Nurs Res. · Pubmed #15695580 No free full text.

Abstract: As interest in complementary and alternative therapies grows, nurses can expect to be asked for advice regarding their use, but there are few clinical studies on which nurses can base their responses. Conducting research with complementary therapies is therefore important for nursing, but there are some pitfalls in doing research with these products, particularly if one is using standard clinical-trials methods. In this article, the authors outline some of those pitfalls based on their experience conducting a clinical trial to examine the effects of elk velvet antler on symptoms of rheumatoid arthritis. They discuss design issues related to justification, method, and ethics and explore some important regulatory issues of which nurses should be aware. Some recommendations are presented to help nurses engaging in such research to avoid problems that could interfere with the smooth conduct of their studies.

Ou Y, Enarson P, Rattner JB, Barr SG, Fritzler MJ. · Department of Anatomy and Cell Biology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada. · Clin Exp Immunol. · Pubmed #15086405 links to  free full text

Abstract: We studied the autoantigen targets of 75 human sera that had antibodies to the nuclear envelope (NE) as identified by indirect immunofluorescence (IIF) on HEp-2 cells. Several different IIF staining patterns could be identified when antibodies to different components of the nuclear membrane (NM) and nuclear pore complexes (NuPC) were identified: a smooth membrane pattern characteristic of antibodies to nuclear lamins, a punctate pattern typical of antibodies to the nuclear pore complex and more complex patterns that included antibodies to nuclear and cytoplasmic organelles. Western immunoblotting of isolated nuclear and NE proteins and immunoprecipitation of radiolabelled recombinant proteins prepared by using the full-length cDNAs of the Translocated promoter region (Tpr), gp210 and p62 were used to identify specific autoantibody targets. Fifty-two of the 75 (70%) sera bound to Tpr, 25 (33%) bound to lamins A, B or C, 15 (20%) reacted with gp210 and none reacted with p62. Sixteen (21%) did not react with any of the NE components tested in our assays. The clinical features of 37 patients with anti-NE showed that there were 34 females and three males with an age range of 16-88 years (mean 59 years). The most frequent clinical diagnosis (9/37 = 24%) was autoimmune liver disease (ALD; two with primary biliary cirrhosis), followed by seven (19%) with systemic lupus erythematosus (SLE), four (11%) with a motor and/or sensory neuropathy, three (8%) with anti-phospholipid syndrome (APS), two with systemic sclerosis (SSc), two with Sjögren's syndrome (SjS), and others with a variety of diagnoses. This report indicates that Tpr, a component of the NuPC, is a common target of human autoantibodies that react with the NE.

Kaplan G, Panaccione R. · Inflammatory Bowel Disease Center, University of Calgary, Alberta, Canada. · Inflamm Bowel Dis. · Pubmed #15058529 No free full text.

This publication has no abstract.