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ID PMID Title PublicationDate abstract
17101541 Interfering with leukocyte integrin activation--a novel concept in the development of anti 2006 Inflammation is a crucial response against invading pathogens, in which immune cells, including neutrophils and T cells, are recruited into tissue from the bloodstream to help clear infection. However, a prevailing inflammatory response where the immune cells attack healthy tissue is associated with many diseases, including asthma, rheumatoid arthritis, atherosclerosis and multiple sclerosis. Integrins are key players in the recruitment of immune cells from the bloodstream into tissues, and are thus therapeutic targets for intervention with inflammatory responses. Thus far, mainly extracellularly acting therapeutics (monoclonal antibodies) have been developed against integrins, targeting ligand binding sites in these heterodimeric adhesion receptors. However, since these therapeutics nonselectively block all integrin functions, some side effects are expected and have been observed. Therefore, novel concepts need to be developed in the therapeutic targeting of integrins. Recently, major advances have been made in the understanding of integrin biology. Integrin structures have been solved by X-ray crystallography, revealing unexpected data about the activation mechanism of integrins in cells. Additionally, several intracellular factors in the integrin activation process have been identified, providing potential specific targets for therapeutic intervention. Here, we present key events and players in leukocyte integrin activation, and discuss potential new drug targets in the prevention of inflammatory disease.
17080203 The role of galactosyltransferases in cell surface functions and in the immune system. 2006 Sep The immune system relies on cellular communication and often on the recognition of carbohydrates by mammalian lectins. Galactose (Gal)-containing structures are involved in both the innate and adaptive immune systems. Gal is a ligand for Gal/N-acetylgalactosmine (GalNAc) receptors and galectins, and is part of the scaffold structure that synthesizes oligosaccharide ligands for selectins, siglecs and other lectins of the immune system. Gal residues are added to glycoproteins and glycolipids by members of a large family of galactosyltransferases. The expression of many of these enzymes is regulated by the action of cytokines, and becomes altered in various disease states. Specific galactosyltransferases have been shown to control cell adhesion and leukocyte functions. Antibodies need to be galactosylated for normal function, and undergalactosylated immunoglobulin (Ig) is associated with rheumatoid arthritis, while Gal is lacking in the IgA of patients with IgA nephropathy. Interactions involving Gal play important roles in host defenses; they can also result in serious pathophysiology. Galactosyltransferases represent potential targets for the control of cell growth and apoptosis, inflammation and infections.
17039336 [Insoles for the rheumatic foot. A clinical and pedobarographic analysis]. 2006 Nov BACKGROUND: Insoles are regarded as an appropriate tool for the management of rheumatic foot disorders. However, a quality control for this purpose has not been established. In our study, the clinical effectiveness of insoles used in patients with rheumatic foot disorders was addressed. In addition, we sought to establish pedobarography as a means of quality control for orthotic management of the rheumatic foot. MATERIAL AND METHODS: Our study included 20 rheumatoid arthritis patients with painful rheumatic foot deformities who were provided with insoles. Clinical data were obtained by physical examination and a 100-mm pain scale. Pedobarography was performed using the novel pedar cable system with new and individually designed insoles and after a 6-month follow-up. A shoe-only trial served as control. The parameters maximum force, peak pressure, force-time integral, and average pressure were analyzed in anatomical regions and an individually defined overloaded forefoot region. RESULTS: Clinical improvement was significant after a 6-month follow-up in spite of a heterogeneous group of patients. However, our results could not confirm consistent changes in plantar pressure distribution. CONCLUSION: As a conclusion, further efforts are necessary to establish a quality control for orthotic management of the rheumatic foot.
17003846 Analgesic, antiinflammatory, and ulcerogenic studies of meloxicam solid dispersion prepare 2006 Sep Meloxicam is a nonsteroidal antiinflammatory drug, used in the treatment of rheumatoid arthritis and oestoarthritis. It is practically insoluble in water, leading to poor dissolution, variations in bioavailability, and gastric irritation on oral administration. In the attempt to reduce its gastric side effect and to increase aqueous solubility, physical mixture and solid dispersion of the drug were prepared with polyethylene glycol 6000. The analgesic, antiinflammatory, and ulcerogenic effects were assessed for physical mixture and solid dispersion in comparison with meloxicam alone. The results indicate that both physical mixture and solid dispersion possess better analgesic and antiinflammatory properties with less ulcerogenic potential when compared with pure meloxicam.
16842224 Antioxidants and inflammatory disease: synthetic and natural antioxidants with anti-inflam 2006 Jul Oxidants play a significant role in the pathogenesis of a number of disorders such as inflammation, rheumatoid arthritis, asthma, psoriasis and contact dermatitis leading to oxidative stress. Oxidative stress may be defined as an imbalance between cellular production of reactive oxygen species (ROS) and antioxidant defense mechanisms. ROS (e.g., superoxide radical, peroxynitryl, hydroxyl radical and hydrogen peroxide) are constantly produced as a result of metabolic reactions in living systems. The aim of this review is to describe recent developments in the study of antioxidants and their role in preventing the formation of ROS. The processes associated with inflammatory responses are complex and often involve ROS. There are many mediators, which initiate and amplify the inflammatory response such as histamine, serotonin, pro-inflammatory cytokines (interleukin-1B (IL-1b) and tumor necrosis factor (TNF-alpha), inflammatory cells (leukotrienes, macrophages), metabolic products of arachidonic acid (thomboxane A(2), prostaglandins and leukotrienes). The first part of this review focuses on the role of ROS in inflammation. The second part concerns synthetic antioxidants with antiinflammatory activity, and the third part addresses naturally occurring antioxidants with antiinflammatory activity.
16829986 Biologics targeted at TNF: design, production and challenges. 2006 Apr Several biotech-derived drugs aimed at Tumor Necrosis Factor (TNF) have been licensed in the last years, profoundly changing the therapy of several autoimmune diseases based on inflammation, affecting the life of patients and bringing to the market attention the growth potentials of biologics directed at cytokines. The proof of principles that led to the design of these compounds dates back from the nineties, when the involvement of TNF in rheumatoid arthritis was proved by the ability of specific anti-TNF proteins to modulate the inflammatory response in animal models. Monoclonal antibodies aimed at neutralizing the excess TNF were developed with therapeutic purposes, and a chimeric and a full human antibody are now approved for several clinical indications. The design of soluble receptors able to bind and neutralize human TNF paralleled the development of antibodies as therapeutics, and the clinical success of these drugs was achieved by the clever design of a novel recombinant dimeric protein, consisting of the extracellular portion of human TNF receptor linked to the constant portion of a human immunoglobulin. All approved biologics designed to bind and neutralize TNF were obtained through the power of biotechnological methods: the development of these important biopharmaceutical products, their means of production and the challenges they face will be analyzed here in details.
16803617 The Autoimmune Disease Database: a dynamically compiled literature-derived database. 2006 Jun 27 BACKGROUND: Autoimmune diseases are disorders caused by an immune response directed against the body's own organs, tissues and cells. In practice more than 80 clinically distinct diseases, among them systemic lupus erythematosus and rheumatoid arthritis, are classified as autoimmune diseases. Although their etiology is unclear these diseases share certain similarities at the molecular level i.e. susceptibility regions on the chromosomes or the involvement of common genes. To gain an overview of these related diseases it is not feasible to do a literary review but it requires methods of automated analyses of the more than 500,000 Medline documents related to autoimmune disorders. RESULTS: In this paper we present the first version of the Autoimmune Disease Database which to our knowledge is the first comprehensive literature-based database covering all known or suspected autoimmune diseases. This dynamically compiled database allows researchers to link autoimmune diseases to the candidate genes or proteins through the use of named entity recognition which identifies genes/proteins in the corresponding Medline abstracts. The Autoimmune Disease Database covers 103 autoimmune disease concepts. This list was expanded to include synonyms and spelling variants yielding a list of over 1,200 disease names. The current version of the database provides links to 541,690 abstracts and over 5,000 unique genes/proteins. CONCLUSION: The Autoimmune Disease Database provides the researcher with a tool to navigate potential gene-disease relationships in Medline abstracts in the context of autoimmune diseases.
16678704 Giant-cell temporal arteritis in a 17-year-old male. 2006 May Temporal arteritis, particularly in its classic form, is exceedingly rare in individuals <50 years old. We report the youngest case of biopsy-proven giant cell temporal arteritis. A 17-year-old male presented with a progressively expanding and pulsatile but otherwise asymptomatic mass in his forehead. The patient's medical history was significant for uveitis since the age of 3, and severe allergic rhinitis, mild asthma, and juvenile rheumatoid arthritis as a young adolescent. Admission laboratory values included a mildly elevated erythrocyte sedimentation rate and C-reactive protein level. A computed tomography evaluation demonstrated aneurysmal degeneration of the frontal branch of the right superficial temporal artery and confirmed no other cerebrovascular changes. Histologically, the aneurysmal arterial segment demonstrated subacute temporal arteritis. The arterial wall had a primarily lymphoplasmacytic infiltrate with rare giant cells and focally marked medial destruction. Additionally, severely obstructive intimal hyperplasia with chronic adventitial and periadvential dense fibrosis was noted. The diagnosis of classic giant cell temporal arteritis was established from the biopsy result. Postoperatively, the patient was treated with prednisone for 3 months. Three years after surgery, the patient remains well and reports no recurrence of temporal artery disease.
16567355 The ICF comprehensively covers the spectrum of health problems encountered by health profe 2006 Oct OBJECTIVES: The objective of this study was to investigate, whether the International Classification of Functioning, Disablity and Health (ICF) comprehensively covers the spectrum of health problems encountered by medical doctors and physiotherapists in patients with musculoskeletal conditions. METHODS: A worldwide e-mail survey with questionnaires that requested lists of relevant areas in the ICF components-body functions, body structures, activities and participation, and environmental factors-in patients with rheumatoid arthritis, osteoarthritis, low back pain and osteoporosis was conducted. The suitability of linking the named concepts to the ICF as well as the precision of the linking was characterized by assigning the concepts to six groups. RESULTS: All concepts that were named by the experts could be linked to the ICF, with the exception of personal factors. Between 32% (environmental factors) and 51% (activities and participation) of the named concepts were linked to an ICF category with an identical meaning and the same grade of precision. All other named concepts were linked to ICF categories with a lower level of precision, or encompassed more than one ICF category, or were linked to an ICF category with a related, but not identical meaning. CONCLUSIONS: The ICF covers comprehensively the spectrum of problems encountered in patients with musculoskeletal conditions by clinical experts throughout the world. This strengthens the validity of the ICF in the view of the users and will encourage the use of ICF-based applications such as the ICF checklist and the now-developed ICF Core Sets.
16513409 High-mobility group box 1 (HMGB1) protein: friend and foe. 2006 Jun HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.
16504830 Newer therapeutic approaches to the vasculitides: biologic agents. 2006 Feb Biologic therapies have emerged as important treatments in chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, and are now garnering more attention in the vasculitides. These agents, including tumor necrosis factor-alpha inhibitors, B-cell-depleting agents, interferon-alpha, and some antiviral treatments, target specific components of the immune system and may have lower side effect risk profiles than the conventional immunosuppressives and cytotoxic agents. This article addresses the encouraging data and the possible pitfalls of these new therapeutic options, thus far evaluated mostly by case reports, small series, and open-label trials. Confirming the efficacy of existing and newer therapies will require further clinical investigation through randomized placebo-controlled studies to identify the proper doses and treatment schedules and single out those drugs that may expose patients to dangers that outweigh the potential benefits.
16480261 Dual binding mode of a novel series of DHODH inhibitors. 2006 Feb 23 Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.
16450687 Periprosthetic fractures of the humerus. 2005 Dec Periprosthetic humeral fractures present a treatment challenge for the orthopedic surgeon. The overall incidence of fracture is between 0.5% and 3%, with the majority of fractures occurring intraoperatively and involving the humeral diaphysis. Excess torque produced during surgery is usually responsible for intraoperative fractures. Improper canal preparation or prosthetic placement may also increase the chance of sustaining a fracture. Postoperative fractures are most commonly caused by minor trauma, such as a fall. Poor bone quality, female sex, advanced age, and history of rheumatoid arthritis are the risk factors most commonly associated with periprosthetic fractures. All 4 systems used to describe periprosthetic humeral shaft fractures classify fracture patterns according to the anatomic relation of the fracture to the prosthetic stem. Treatment decisions should be made with respect to obtaining fracture stability, initiating early gleno-humeral motion, and restoring shoulder function. Intraoperative fractures and any postoperative fracture resulting in prosthetic instability should be treated with a long-stem prosthesis extending at least 2 to 3 cortical diameters past the fracture site with consideration for rigid plate fixation. Short oblique or transverse postoperative fractures should be managed with early stable fixation. There has been some support for conservative treatment of long oblique or spiral postoperative fractures. Postoperative diaphyseal fractures distal to the stem generally are well maintained with standard fracture management.
16448842 The SHAP-hyaluronan complex in serum from patients with chronic liver diseases caused by h 2006 Mar Our previous study suggested that the serum-derived hyaluronan associated protein (SHAP)-hyaluronan (HA) complex in the sera of patients with rheumatoid arthritis is useful as a marker that directly correlates with the degree of inflammation. Here, we have investigated the serum levels of the SHAP-HA complex in patients at various clinical stages of chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) caused by infection with the hepatitis C or hepatitis B virus. Both serum levels of the SHAP-HA complex and HA in those patients were significantly higher than those of the controls and increased in the order of CH
16406714 Unresponsiveness of C-reactive protein in the non-infectious inflammation of systemic lupu 2006 Jun C-reactive protein (CRP) response is abnormal to a non-infectious inflammation in systemic lupus erythematosus (SLE). We evaluated the role of cytokines in this CRP unresponsiveness. The sera of 138 SLE patients and 71 rheumatoid arthritis patients were collected prospectively. SLE with infection had higher WBC count, ESR, CRP and C4 levels than those without infection. IL-6, IL-10 and IFN-gamma levels were higher in SLE with infection than SLE without infection. In SLE with infection, the CRP was correlated with the IL-6 (r = 0.77, P < 0.001) but not correlated with IL-10 and IFN-gamma. These data suggest that IL-6 may have a role in the unresponsiveness of CRP to a non-infectious inflammation of SLE.
16367941 Expression of OX40 (CD134) on CD4+ T-cells from patients with myasthenia gravis. 2006 Jan Myasthenia gravis (MG) is commonly regarded as the prototype of an antibody-mediated, organ-specific autoimmune disease. Antibodies against the acetylcholine receptor (AChR) on the muscle endplate trigger its typical clinical manifestations of weakness and fatiguability. T-B cell interactions are thought to play a crucial role in the pathogenesis of MG. OX40 (CD134), a costimulatory molecule that is expressed on activated CD4+ T-cells, might contribute to the development or pathogenesis of immune-mediated diseases such as rheumatoid arthritis and graft-versus-host disease. In the present study, we investigated the expression of OX40 on CD4+ T-cells from patients with MG and healthy individuals. Results from 36 MG patients and 28 healthy controls revealed that more freshly isolated CD4+ T-cells from MG patients expressed OX40 than cells from healthy individuals. High levels of antibodies against the AChR, thymic hyperplasia and onset at an early age were associated with elevated expression of OX40. Upon activation by various concentrations of anti-CD3 antibodies, CD4+ T-cells from MG patients showed a tendency toward higher levels of OX40 expression than cells from healthy individuals. Given the role of OX40 in the immune system, we conclude that OX40 might contribute to the development of MG.
16286433 Searching bibliographic databases for literature on chronic disease and work participation 2006 Jan BACKGROUND: The work participation of people with chronic diseases is a growing concern within the field of occupational medicine. Information on this topic is dispersed across a variety of data sources, making it difficult for health professionals to find relevant studies for literature reviews and guidelines. AIM: The goal of this project was to identify bibliographic databases and search terms that could be most useful for retrieving relevant studies on this topic. METHODS: Five broad questions regarding work participation and chronic disease were formulated, focusing on angina pectoris, depression, diabetes mellitus, hearing impairment and rheumatoid arthritis. A search strategy for retrieving information on these questions was developed and run in five bibliographic databases: Medline, EMBASE, PsycINFO, Cinahl and OSHROM. Relevant publications were selected from the search results. The utility of the selected databases and search terms was evaluated by analysing the number of relevant publications that were retrieved. RESULTS: The number of relevant publications retrieved from each database varied. Most (84%) of the relevant publications that were retrieved from each database were unique to that source. For each database, specific search terms for the concept of 'work' were useful for retrieving relevant publications. CONCLUSION: Medline, EMBASE and PsycINFO are useful databases for quick searches. Useful search terms for the concept of 'work' are work capacity, work disability, vocational rehabilitation, occupational health, sick leave, absenteeism, return to work, retirement, employment status and work status. For comprehensive searches, we recommend additional searches in Cinahl and OSHROM, adapting the search terms to specific databases.
16213276 Effect of amyloidosis on long-term survival in kidney transplantation. 2005 Sep Amyloidosis is characterized by the accumulation of an amorphous material in various organs and tissues secondary to a variety of inflammatory, immune, infectious, and hereditary diseases. Since 1975, our transplantation team has performed 1470 renal transplantations. Between 1985 and July 2004, among 1159 kidney transplantations, 953 (82.3%) were from living donors and 206 (17.7%) from cadaveric donors. There were 32 recipients (28 men, 4 women; mean age, 31.4 +/- 1.7 years; range, 21 to 48 years) with amyloidosis, including, 28 (87.5%) who received grafts from living donors and 4 (12.5%) from cadaveric donors. Amyloidosis was secondary to familial Mediterranean fever in 22 (68.7%) patients and rheumatoid arthritis in 1 (3.1%). The remaining 9 (28.1%) patients had primary amyloidosis. The mean follow-up time was 51.2 +/- 5.7 months (range, 2-124 months). Mean HLA mismatch rate was 2.2 +/- 1. Twenty-six (81.2%) patients are alive at this time with functioning grafts, and a mean serum creatinine value of 2.1 +/- 1.5 ng/dL. The 1- and 5-year patient and graft survival rates were 90.6% and 84.3%, and 81.2% and 68.7%, respectively. We conclude that patients with amyloidosis may undergo kidney transplantation safely expecting outcomes similar to those patients who receive transplantations for other reasons.
16131870 Total femur replacement procedures in tumor treatment. 2005 Sep Replacement of bone segments after resection of a tumor-containing bone has a long history, and currently metallic implants and allografts have reasonable rates of success in terms of patient survival and restoration of useful function. Total femoral resections for extensive tumors are uncommon but clearly represent a major problem, which in the past has required hip disarticulations. In recent years, resection and replacement using custom metallic implants and more recently modular devices have allowed the patients to be restored to reasonable function. Allografts have not been used commonly for this purpose. During the past 23 years, we have done 15 total femoral replacements for osteosarcoma, chondrosarcoma, metastatic carcinoma, and an osteonecrotic fractured femur in a patient with rheumatoid arthritis and for a patient with severe deformity based on Paget's disease. Ten of these patients had allografts implanted with total hip replacement and total knee replacement implants and five patients had metallic implants. Eight of the patients died from disease, but the remaining seven have done reasonably well in terms of function and absence of complications such as fracture or infection. None of the patients required an amputation. The procedure is complex and metallic implant and allograft implantation require wide surgery and special systems of reconstruction. LEVEL OF EVIDENCE: Therapeutic study, Level IV-1 (case series). See the Guidelines for Authors for a complete description of levels of evidence.
16101827 Mechanisms of lymphocyte migration in autoimmune disease. 2005 Sep 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.