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ID PMID Title PublicationDate abstract
17043550 Basic science for the clinician 33: interleukins of current clinical relevance (part I). 2004 Dec Normal orchestration of wound healing, the protective immune response and inflammation, involve a bewildering array of cells that communicate to each other locally by means of cell-surface receptors and their ligands. For local and middle- to long-distance coordination, some of these same cells make and export soluble messengers that communicate to both immune and nonimmune cells. Although all these messengers have a role in normal immune homeostasis, it is apparent that many are involved in tissue damage in a variety of diseases, eg, rheumatoid arthritis and osteoarthritis. Some of these molecules are known as interleukins. The list of interleukins (IL) is now nearing 30 and, as a result of the molecular biology revolution, we now know the direct clinical relevance of many of them. As benchtop molecular biology matures into therapeutic and diagnostic tools, clinicians must begin to master this disparate group of molecules; making this harder is the fact that unlike acronyms (often impenetrable as they might be), an IL designation does not give a clue as to the source, target, or action of the IL. IL-1 and IL-2 were the first messengers to bear the "interleukin" name 25 years ago; they are well known to rheumatologists by now, so this article deals with some of the characteristics of the other clinically relevant IL molecules starting with IL-3.
15578948 Ribozyme- and deoxyribozyme-strategies for medical applications. 2004 Nov Ribozymes are catalytically active nucleic acids capable of site-specific cleavage of target mRNAs. They have widely been employed as tools in functional studies and for therapeutic purposes. Different classes of ribozymes distinguished by size and mechanism of action have been discovered in natural systems or obtained by in vitro selection. After an introduction to different types of ribozymes with a special focus on the hammerhead and hairpin ribozyme, major challenges in the process of developing ribozymes for medical purposes will be described in the present review. Subsequently, examples of ribozyme applications in animal models for various diseases including cancer, viral infections, rheumatoid arthritis and cardiovascular diseases will be given. The course of phase I and II clinical trials with ribozymes designed to treat patients with virus infections or cancer will be outlined. Finally, the current significance of ribozymes will be discussed in the light of the emergence of new powerful anti-mRNA strategies, particularly RNA interference (RNAi).
15245375 Haplotype variation at the IBD5/SLC22A4 locus (5q31) in coeliac disease in the Irish popul 2004 Aug In addition to the well-established association of coeliac disease (CD) with HLA-DQ (6p21) and possibly CTLA4 (2q33), there is considerable evidence for a susceptibility locus on chromosome 5q, which contains many potential candidates for inflammatory disease, including a cluster of cytokine genes in 5q31. CD cases and controls were genotyped for four single-nucleotide polymorphism (SNP) markers that together characterize >90% of the haplotype variation at the IBD5 locus encoding, among others, the SLC22A4 gene. IBD5 and SLC22A4 map to 5q31 and have recently been associated with Crohn's disease and rheumatoid arthritis. Haplotype frequencies do not differ significantly between CD cases and controls in the Irish population, and therefore the chromosome 5 CD susceptibility locus most likely lies elsewhere on 5q.
15230295 CTLA4Ig: a novel inhibitor of costimulation. 2004 T cell costimulatory pathways are believed to play important roles in the pathogenesis of various autoimmune diseases including systemic lupus erythematosus (SLE). Animal models of SLE support the role of T cell costimulation in B cell activation and the production of autoantibodies. CTLA4Ig is a novel fusion protein that interferes with T cell costimulation by inhibiting the CD28-B7 interaction. A pivotal study demonstrated the ability of CTLA4Ig to suppress the production of anti-dsDNA antibodies and decrease nephritis in lupus prone mice. In an additional study, the combination of CTLA4Ig and cyclophosphamide significantly reduced proteinuria and prolonged survival in mice with advanced nephritis. In small human studies of psoriasis and rheumatoid arthritis, CTLA4Ig improved clinical outcomes and was well tolerated. These promising experiences with CTLA4Ig have paved the way for future studies in human SLE.
15025285 Pure red cell aplasia--report of 11 cases from eastern Nepal. 2003 Jul There were eleven cases of pure red cell aplasia diagnosed over a period of 2 years (January 2000-December 2001). All the patients had anemia with pallor and weakness being the presenting complaints. Hematological profile depicted normocytic normochromic anemia, reticulocytopenia and marked paucity of erythroid precursors on bone marrow aspiration and biopsy studies. In the present study, one case was of congenital pure red cell aplasia, in one other case of pyrexia of unknown origin, no definitive diagnosis could be made. Other associated diseases seen with pure red cell aplasia were thymoma, septicemia, protein energy malnutrition, non-Hodgkin's lymphoma, juvenile rheumatoid arthritis, acute myeloid leukemia, tuberculosis and hepatitis C. The association of pure red cell aplasia with haematologic malignancies is rare. There are very few case reports on pure red cell aplasia with hepatitis C.
14713400 Gene therapies for osteoarthritis. 2004 Feb Osteoarthritis (OA) is a major health problem in urgent need of better treatment. Gene therapy offers to meet this need. Of the different strategies for using gene therapy in OA, local gene transfer to synovium is in the most advanced stage of development. Local gene transfer brings several advantages, including a focused, local therapy that promises greater efficacy with reduced side-effects, potentially at far lower cost. Moreover, its clinical feasibility has already been confirmed in two Phase I studies of gene therapy for rheumatoid arthritis. Although there are numerous candidate genes of potential use in treating OA genetically, considerable evidence identifies interleukin-1 (IL-1) as a key target. The existence of a natural antagonist, the IL-1 receptor antagonist (IL-1Ra), provides a means with which to inhibit its biologic actions. Clinical studies are suggested in which IL-1Ra complementary DNA is transferred to knee joints shortly before they are surgically replaced with prostheses. This will permit the ready assessment of the safety and efficiency of gene transfer and expression in the human OA knee, as well as permitting preliminary functional data to be obtained, as a prelude to phase II efficacy studies. At this point, the major barriers to progress are financial rather than intellectual or technical.
12967328 Corticosteroid-insensitive asthma: molecular mechanisms. 2003 Sep Corticosteroids are the most potent anti-inflammatory agents used to treat chronic inflammatory diseases such as bronchial asthma. However, there are a small number (<5%) of asthmatic patients who do not respond well, or at all, to corticosteroid therapy - the corticosteroid-resistant and corticosteroid-dependent patients. Although this phenomenon is relatively uncommon, it poses a difficult therapeutic problem because few alternative therapies are available and these patients account for >50% of the health care costs of asthma. If the mechanisms for corticosteroid insensitivity are understood they may, in turn, provide insight into the key mechanism of corticosteroid action and allow a rational way to treat these individuals whose disease tends to be severe. Corticosteroid insensitivity is not limited to asthma and is a feature of other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Thus, elucidation of the cause for the relative lack of corticosteroid response in this subgroup of asthmatic individuals may have important implications for other diseases.
12965278 Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. 2003 Sep Tumour necrosis factor alpha (TNFalpha), named for its antitumour properties, was isolated almost 30 years ago. It is a vital member of the multifunctional TNF superfamily and has important roles in immunity and cellular remodelling as well as influencing apoptosis and cell survival. Its central role in inflammation has led to the development of TNFalpha antagonists as effective therapies for rheumatoid arthritis and inflammatory bowel disease. In this review, we discuss the evidence which has accumulated during the past decade that implicates TNFalpha in inflammatory pathways that increase tumorigenesis. There is convincing evidence that under specific conditions TNFalpha is a tumour promoter and helps to produce the toxic effects associated with conventional cancer therapy, such as the cytokine release syndrome and cisplatin-induced nephrotoxicity. Several trials have been set up to investigate the role of TNFalpha antagonists in cancer. It is hoped that these agents inhibit the neoplastic process either alone or in combination with other agents, and ameliorate the side effects of cancer therapy.
12943459 Drug discovery for inflammatory diseases. 2003 Sep Drug Discovery for Inflammatory Diseases was a 3-day conference organised by the IBC Life Sciences as part of their Drug Discovery Series. The meeting featured a keynote presentation by Edward Keystone (University of Toronto) on the new strategies in managing rheumatoid arthritis, followed by five themed sessions: protein kinase inhibition, cytokines, chemokines, Toll-like receptors/innate immunity and transcription factors. The programme included a good mix of speakers from academia and biotechnology, and covered a wide spectrum of topics, ranging from developing strategies to suppress immune responses in autoimmune and inflammatory diseases, to novel means of stimulating the immune system for vaccine development and cancer therapy. Fundamental basic science questions were addressed along with the new approaches to drug design and clinical studies. Overall, the meeting included over 25 presentations, and there was ample time to exchange ideas in an informal setting. This review will focus on five talks representing three different areas of research: the role of an unusual cytokine, leptin, in autoimmunity; targeting of Toll-like receptors in vaccine development and in cancer therapy; and the molecular dissection of glucocorticoid-mediated repression and of selective glucocorticoids with anti-inflammatory activities.
12565702 Targeting G protein-coupled A2a adenosine receptors to engineer inflammation in vivo. 2003 Apr G protein-coupled adenosine receptors are the subject of intense study as immunomodulators of inflammation especially since the recent demonstration that the A2a receptor acts to down-regulate inflammation and inhibit tissue damage in vivo [Nature 414 (6866) (2001) 916]. The adverse effects of overactive inflammation are evident in diseases e.g. sepsis, rheumatoid arthritis, and multiple sclerosis underscoring the importance of inhibiting inflammation or selectively enhancing inflammatory processes. It has been shown recently that the A2a adenosine receptor is a critical component of an endogenous "immunosuppressive loop" in which extracellular adenosine that accumulates due to local hypoxia caused by inflammatory insult signals through cAMP-elevating A2a receptors in a delayed negative feedback manner. Understanding how tissues regulate inflammation will provide the information necessary to allow for the engineering, or selective targeting, of endogenous inflammatory pathways. Recognition of A2a receptors as "natural" or endogenous brakes of inflammation provides the intellectual scaffolding needed to pursue these goals.
12541028 Perforated duodenal ulcer associated with an incarcerated hiatal hernia: report of a case. 2002 We report the case of a perforated duodenal ulcer and diffuse peritonitis associated with an incarcerated hiatal hernia. A 77-year-old woman with a 17-year history of rheumatoid arthritis treated with nonsteroidal anti-inflammatory drugs, who had also been receiving treatment for non-Hodgkin's lymphoma over 4 years, was referred to us for investigation of nausea and vomiting. An abdominal compute tomography (CT) scan showed an incarcerated hiatal hernia and free air in the hernia sac. Emergency laparotomy revealed an incarcerated hiatal hernia involving the stomach, transverse colon, and omentum. A perforated ulcer was also found in the posterior wall of the first portion of the duodenum. The combination of these disorders is thought to be rare in patients with a hiatal hernia and free air in its sac. As the reported mortality of perforated gastric ulcer associated with a hiatal hernia is high, early elective surgery should be performed in patients with a duodenal ulcer associated with a hiatal hernia.
12498005 Tacrolimus Fujisawa. 2002 Sep Fujisawa has launched the immunosuppressant tacrolimus extensively for use in organ transplantation. The compound has also been developed for the treatment of atopic dermatitis, for which it has been launched in the US, Japan, Switzerland, Canada and Germany [425053], [426616], [435668], [447770]. Tacrolimus has also been developed for chronic rheumatoid arthritis (RA) and several other autoimmune diseases [351891], [352195], [360717]. By March 2002, tacrolimus had entered phase III trials for inflammatory bowel disease (IBD) in Japan [442503]. This evaluation will focus on the development of tacrolimus for this indication.
12402411 Cardiac involvement in systemic autoimmune diseases. 2002 Dec The heart and the vascular system are frequent and characteristic targets of several systemic autoimmune diseases, in particular Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc). In this chapter we review the classic cardiac abnormalities and the more recent data about cardiovascular involvement as part of a major disease complication determining a substantial morbidity and mortality. In addition to the classic cardiac abnormalities involving the heart structures, acute and chronic ischemic heart disease and cerebrovascular accidents are threatening clinical manifestations of SLE and RA associated to an early accelerated atherosclerosis. Immune-mediated inflammation is now recognized as an important factor involved in the pathogenesis of atherosclerosis. Ongoing clinical studies are being devised to find specific risk factors associated with systemic autoimmune diseases and/or treatment regimens. Hopefully, prophylactic measures should be available within the next few years.
12907325 The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both e 2003 Aug OBJECTIVES: Etoricoxib is a selective cyclooxygenase inhibitor that in clinical studies has improved the signs and symptoms of osteoarthritis and rheumatoid arthritis and reduced the potential for GI injury. The incidence of endoscopically detected ulcers and of clinically important upper GI events (perforations, ulcers, and bleeding episodes) was compared in patients taking etoricoxib or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Upper GI endoscopy was performed at intervals over 12 wk in 680 patients taking etoricoxib 120 mg once daily, ibuprofen 800 mg three times daily, or placebo in a randomized, parallel-group, double-blind study. Survival analysis was used to analyze time-to-event data for the incidence of gastric or duodenal ulcers (> or =3 mm and > or =5 mm), and the log rank test was used to compare the cumulative incidence between treatment groups. A combined analysis of upper GI events in all 10 Phase II/III clinical trials of etoricoxib (60, 90, or 120 mg) versus nonselective NSAIDs (naproxen, ibuprofen, or diclofenac) for osteoarthritis, rheumatoid arthritis, and chronic low back pain was conducted. Investigators reported potential events for adjudication by an external, blinded committee, using prespecified criteria to confirm events. All events that occurred during active treatment periods (maximum 792 days) or within 14 days of stopping treatment were included in the analysis. Time to first event was evaluated using survival analysis; the Kaplan-Meier method was used to determine the cumulative incidence, and relative risk was estimated with the Cox proportional hazards model. RESULTS: In the endoscopy study, the cumulative incidence of ulcers >/=3 mm at 12 wk in the ibuprofen group (17%) was significantly higher than in the etoricoxib group (8.1%, p < 0.001); similar results were seen for ulcers >/=5 mm. In the placebo group, the rate of ulcers >/=3 mm was 1.86%. Of 3142 patients treated with once-daily etoricoxib and 1828 patients treated with a nonselective NSAID (ibuprofen, naproxen, or diclofenac), 82 patients with investigator-reported upper GI events (71 confirmed) were eligible for the combined analysis. For etoricoxib versus NSAIDs, the rate per 100 patient-yr for confirmed events was 1.16 versus 3.05 (relative risk = 0.44, 95% CI = 0.27-0.72, p < 0.001), whereas that for investigator-reported events was 1.35 versus 3.42 (relative risk = 0.47, 95% CI = 0.30-0.74, p = 0.001). Results were driven primarily by studies with naproxen as the comparator. CONCLUSIONS: The incidence of endoscopically detected ulcers was significantly lower with etoricoxib 120 mg than with ibuprofen 2400 mg. Treatment with etoricoxib reduced the incidence of investigator-reported and confirmed adverse upper GI events by approximately 50% compared with treatment with nonselective NSAIDs.
15584484 Genetic analysis of SLC11A1 polymorphisms in multiple sclerosis patients. 2004 Dec Solute carrier 11a1 (SLC11A1; formerly NRAMP1, where NRAMP stands for natural resistance-associated macrophage protein) is a proton/bivalent cation antiporter that localizes to late endosomes/lysosomes. SLC11A1 regulates macrophage functions that are of potential importance in the induction and/or maintenance of autoimmune diseases such as rheumatoid arthritis, type I diabetes and Crohn's disease. We investigated SLC11A1 gene as a candidate gene for genetic susceptibility to multiple sclerosis (MS) in our population. Four SLC11A1 gene polymorphisms (5'GT repeat, D543N, 1729 + 55del4 and 1729 + 271del4) were analysed in a case-control study of 195 patients with MS and 125 control subjects. We found no evidence of association between SLC11A1 polymorphisms and MS susceptibility in the Spanish population.
14712386 Two asymmetric contoured plate-rods for occipito-cervical fusion. 2004 May The author presents a retrospective clinical study addressing the outcome after posterior stabilisation of the occipital-cervical spine using a new cranio-spinal implant. The range of surgical methods for operative treatment of occipito-cervical instability remains wide, and it is still a demanding technique that frequently requires improvisation by the surgeon. No previous studies have been published of occipito-cervical reconstructions using two contoured asymmetrical occipital plates interdigitating in the midline at the occiput and allowing various methods of cervical fixation, by means of different hooks, a claw device or screws. Nine patients with severe occipito-cervical instability and/or subaxial malalignment underwent reconstructive surgery with the new implants between 1998 and 2001. Seven patients suffered from rheumatoid arthritis (RA) including cranial settling. Two patients had widespread cervical metastases. All patients suffering RA were treated by preoperative cervical traction for up to 28 days, and intraoperative traction, to try to restore the malalignment. Traction was also used, to diminish pain and to improve neurological symptoms. The lowest vertebra fused was T3. All patients were immobilised with an external orthosis or brace for 6 weeks or 3 months. A solid fusion was achieved in all patients. None of the patients deteriorated postoperatively. No serious complications occurred. One occipital screw broke and one hook loosened, needing a re-fixation. The simplicity of applying these cranio-cervical implants makes them practical for every orthopaedic or neurosurgeon with a special interest in cervical spine surgery.
14710510 Improved education in musculoskeletal conditions is necessary for all doctors. 2003 It is likely that everyone will, at some time, suffer from a problem related to the musculoskeletal system, ranging from a very common problem such as osteoarthritis or back pain to severely disabling limb trauma or rheumatoid arthritis. Many musculoskeletal problems are chronic conditions. The most common symptoms are pain and disability, with an impact not only on individuals' quality of life but also, importantly, on people's ability to earn a living and be independent. It has been estimated that one in four consultations in primary care is caused by problems of the musculoskeletal system and that these conditions may account for up to 60% of all disability pensions. In contrast, teaching at undergraduate and graduate levels--and the resulting competence and confidence of many doctors--do not reflect the impact of these conditions on individuals and society. Many medical students do not have any clinical training in assessing patients with bone and joint problems. Under the umbrella of the Bone and Joint Decade 2000-2010, experts from all parts of the world with an interest in teaching have developed recommendations for an undergraduate curriculum to improve the teaching of musculoskeletal conditions in medical schools. The goal for each medical school should be a course in musculoskeletal medicine concentrating on clinical assessment, common outpatient musculoskeletal problems and recognition of emergencies. Improving competency in the management of musculoskeletal problems within primary care settings through improved education is the next aim, but there are needs for improvement for all professionals and at all levels within the health care system.
14531303 [A case of interstitial pneumonia induced by an ACE inhibitor (temocapril hydrochloride)]. 2003 Sep A 51-year-old woman who had been treated for years for rheumatoid arthritis presented with a persistent dry cough and shortness of breath three weeks after administration of the ACE inhibitor temocapril hydrochloride against essential hypertension. Chest radiography and computed tomography showed diffuse reticular shadows and ground-grass opacities in both lung fields. Bronchoalveolar lavage fluid analysis showed an increase of lymphocytes and CD8+ T cells (93.3% of lymphocytes), and a decrease of the CD4/8 ratio of the T cell subset (0.04). Histopathological analysis of trans-bronchial lung biopsy specimens showed infiltration of lymphocytes into the alveolar septa and exudation of alveolar macrophages, signs characteristic of interstitial pneumonia. A drug lymphocyte stimulation test was positive for temocapril, but negative for other drugs. On the basis of these findings, we diagnosed temocapril hydrochloride-induced interstitial pneumonia.
14526631 [Cutaneous manifestations of internal diseases: purpura, livedo, pyoderma gangrenosum]. 2003 Sep 3 Dermatology and internal medicine have in common that many systemic diseases manifest with skin symptoms that are easily accessible for both diagnostic and investigative procedures. Even if modern practice of medicine tends towards organ specific particularity of specialists, dermatology traditionally strives for interdisciplinary communication. Cutaneous manifestations of internal diseases present in various forms. In a syndrome, a number of symptoms present in an identical pattern, and pattern recognition is diagnostic. Vice versa, a distinct skin sign can be a clue to various internal disorders, that have to be considered in the differential diagnosis. Purpura and livedo due to either inflammatory (immune complex mediated or associated with ANCA) or vasoocclusive microthrombotic vascular disease are presented as examples. Finally, subtile variations in key symptoms of the skin, such as of pyoderma gangrenosum, may give a clue to a specific underlying disease, such as rheumatoid arthritis, inflammatory bowel disease, monoclonal gammopathy, or hematologic disease, as exemplified by the variants of pyoderma gangrenosum.
13680149 Cutaneous warts in patients with lupus erythematosus. 2004 May The aim of this study was to determine the frequency of cutaneous warts (CW) in patients with lupus erythematosus (LE) and evaluate the effect of immunosuppressants on the appearance of CW. Fifty-eight patients with LE, 74 with rheumatoid arthritis (RA), and 105 healthy individuals were interviewed and examined for the presence of CW. All were questioned to find out whether their CW developed before or after onset of the disease or during treatment. Cutaneous warts occurred considerably more often in patients with LE than in healthy control and RA patients ( P<0.003 and P<0.04, respectively). The presence of CW did not correlate with the taking of immunosuppressive drugs. The findings suggest that the high prevalence of CW in patients with LE is probably due to defects in some immune mechanisms, independently of immunosuppressive drugs.