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ID PMID Title PublicationDate abstract
16455071 Free immunoglobulin light chains as target in the treatment of chronic inflammatory diseas 2006 Mar 8 Immunoglobulin free light chains were long considered irrelevant bystander products of immunoglobulin synthesis by B lymphocytes. To date, different studies suggest that free light chains may have important functional activities. For instance, it has been shown that immunoglobulin free light chains can elicit mast cell-driven hypersensitivity responses leading to asthma and contact sensitivity. Free light chains also show other biologic actions such as anti-angiogenic and proteolytic activities or can be used as specific targeting vehicles. Levels of free light chain levels in body fluids increase markedly in diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we will focus on the unexpected biological activities of immunoglobulin free light chains with special attention to its possible role in the induction of chronic inflammatory diseases.
16338343 In vivo imaging of autoimmune disease in model systems. 2005 Autoimmune diseases are characterized by infiltration of the target tissue with specific immune cells that ultimately leads to the destruction of normal tissue and the associated disease. There is a need for imaging tools that allow the monitoring of ongoing inflammatory disease as well as the response to therapy. We discuss new magnetic resonance imaging-based technologies that have been used to monitor inflammation and disease progression in animal models of type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Therapeutic strategies for these diseases include the transfer of immune cells, such as dendritic cells, with the aim of preventing or halting the disease course. We discuss several new MRI labeling techniques developed to allow tracking of immune cells in vivo. These include direct ex vivo labeling techniques as well as the genetic modification of cells to allow them to produce their own contrast agents. This is an area of intense recent research and can be expanded to other conditions such as cancer.
16330513 Constraint in primary total knee arthroplasty. 2005 Dec Instability is an important cause of failure following total knee arthroplasty. Increasing component constraint may reduce instability, but doing so also can cause increased forces to be transmitted to fixation and implant interfaces, which may lead to premature aseptic loosening. Constraint is defined as the effect of the elements of knee implant design that provides the stability needed to counteract forces about the knee after arthroplasty in the presence of a deficient soft-tissue envelope. Determining the amount of constraint necessary can be challenging. Most primary total knee arthroplasties are performed for knees without substantial deformity or the need for difficult ligament balancing; in these cases, either a posterior-stabilized or a posterior cruciate-retaining design is appropriate. In certain situations, such as patients with prior patellectomies, rheumatoid arthritis, or substantial preoperative deformities, a posterior-stabilized knee may be favored. With their large posts, varus-valgus constrained implants typically are reserved for patients with substantial coronal plane instability, which is difficult to balance with a posterior-stabilized or cruciate-retaining implant alone. Rotating-hinge knee implants usually are recommended for patients with severe deformity or instability that cannot be managed with a varus-valgus implant.
16129902 IL-6: from laboratory to bedside. 2005 Jun In the late 1960s, the essential role of T-cells in antibody production was reported. This suggested to us that certain molecules should be released from T-cells for the stimulation of B-cells. We discovered activities in the culture supernatant of T-cells that induced proliferation and differentiation of B-cells. The factor that induced B-cells to produce immunoglobulins was named B-cell stimulatory factor (BSF)-2. The complementary DNA that encoded human BSF- 2 was cloned in 1986. Simultaneously, interferon-beta2 and 26-kDa protein in the fibroblasts were independently cloned by different groups and were found to be identical to BSF-2. Later, a hybridoma/plasmacytoma growth factor and a hepatocyte-stimulating factor also were proven to be the same molecule as BSF-2. Various names were used for this molecule because of its multiple biological activities, and thereafter, these names were unified as interleukin (IL)-6. Since the discovery of IL-6, rapid progress has been made in understanding its actions, the IL-6 receptor system, and the IL-6 signal transduction mechanism. More importantly, it was involved in numerous diseases, such as rheumatoid arthritis and Castleman's disease. By accumulating the basic knowledge, a new therapeutic approach by blocking IL-6 actions appeared to be feasible for chronic inflammatory diseases.
15926118 Autoimmune polyglandular syndrome associated with idiopathic giant cell myocarditis. 2005 May The autoimmune polyglandular syndrome (APS) is characterized by a variable coexistence of several autoimmune diseases, affecting predominantly endocrine glands. In general two types of APS are distinguished. Type 1 APS is an autosomal recessive disorder often leading to insufficiency of the adrenal cortex, the parathyroid glands, and/or the gonads. This type of APS often affects the skin in form of chronic mucocutaneous candidiasis and ectodermal dystrophies (vitiligo, alopecia, keratopathy, dystrophy of dental enamel and nails). The second form of APS is a polygenic disease which usually involves the adrenal gland, the thyroid and the pancreatic beta-cells. In rare cases APS type 2 is associated with myasthenia gravis, autoimmune thrombocytopenic purpura, Sjogren's syndrome or rheumatoid arthritis. Here we describe a case of APS with the unusual combination of type 1 diabetes, secondary adrenocortical insufficiency, growth hormone deficiency, and primary hypothyroidism associated with lethal idiopathic giant cell myocarditis. The combination of APS and idiopathic giant cell myocarditis which is a rare, frequently fatal autoimmune disorder of myocardium affecting most commonly young individuals has not been reported so far.
20477095 Endogenous retroviruses and human disease. 2006 Jan Human endogenous retroviruses (HERVs) constitute up to 8% of the human genome. In general they are highly defective, but complete proviruses have also been described. Over time some transposable elements became inactive, while others retain mobility within the genome. Variably inserting in cellular genes, and differentially within the various allotypes of polymorphic genes, they may have determined inheritable, stable gene modifications. Approximately 40,000 HERV elements have been identified to date, including truncated and solitary long terminal repeats. The latter have powerful transcriptional regulatory properties, therefore they may behave as promoters and enhancers of cellular genes and interact with oncogenes. In some cases, the host has utilized the presence of these ancestrally transmitted foreign genomes to serve physiological functions, and several possible beneficial effects have been reported. On the other hand, links of some human diseases with HERVs are increasingly observed, and this review presents data on possible HERV association to human disease. Reports have shown expression of one or more HERVs in physiological or pathological conditions, in one or more body sites. A key problem is differentiating this expression as cause or effect of a particular disease. Human diseases have been related to HERVs, particularly those characterized by multifactorial etiology or dysregulated immune functions, such as multiple sclerosis, Type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, schizophrenia, cancer and hematological disorders. Convincing evidence has been found that the HERV-W family has a physiological role in early pregnancy and a role in multiple sclerosis as a cofactor and predictor of disease progression. Data available for HERVs and other diseases are attractive, but further studies are required.
15771564 Interleukin-6: from basic science to medicine--40 years in immunology. 2005 This essay summarizes my 40 years of research in immunology. As a young physician, I encountered a patient with Waldenström's macroglobulinemia, and this inspired me to study the structure of IgM. I began to ask how antibody responses are regulated. In the late 1960s, the essential role of T cells in antibody production had been reported. In search of molecules mediating T cell helper function, I discovered activities in the culture supernatant of T cells that induced proliferation and differentiation of B cells. This led to my life's work: studying one of those factors, interleukin-6 (IL-6). To my surprise, IL-6 turned out to play additional roles, including myeloma growth factor and hepatocyte-stimulating factor activities. More importantly, it was involved in a number of diseases, such as rheumatoid arthritis and Castleman's disease. I feel exceptionally fortunate that my work not only revealed the framework of cytokine signaling, including identification of the IL-6 receptor, gp130, NF-IL6, STAT3, and SOCS-1, but also led to the development of a new therapy for chronic inflammatory diseases.
15723007 Heterotopic ossification after primary shoulder arthroplasty. 2005 Jan We have assessed the incidence of heterotopic ossification (HO) after primary shoulder joint replacement in 126 shoulders; 58 patients had hemiarthroplasty, and 68 had total shoulder joint replacement. HO developed to a minor extent in 15% of patients (19/126). There was no statistical difference between hemiarthroplasty or total shoulder replacement or between male and female patients. Patients with cuff tear arthropathy were the only group with an increased risk (36.4% [4/11]) of having HO develop. In patients with osteoarthritis, fractures, or rheumatoid arthritis, HO occurred in less than 14.5% (15/115). Nonsteroidal anti-inflammatory drugs (NSAIDs) did not appear to have any effect on HO as in hip replacement, as HO developed in 15.15% of patients having NSAIDs postoperatively and in 15.05% of patients without NSAIDs. Prophylaxis of HO with NSAIDs seems only to be indicated in patients with cuff tear arthropathy.
16724798 B cell tolerance--how to make it and how to break it. 2006 A series of checkpoints for antigen receptor fitness and specificity during B cell development ensures the elimination or anergy of primary, high-avidity-autoantigen-reactive B cells. Defects in genes encoding molecules with which this purging of the original B cell repertoires is achieved may break this B cell tolerance, allowing the development of B cell- and autoantibody-mediated immune diseases. Furthermore, whenever tolerance of helper T cells to a part of an autoantigen is broken, a T cell-dependent germinal center-type response of the remaining low--or no--autoreactive B cells is activated. It induces longevity of these B cells, and expression of AiD, which effects Ig class switching and IgV-region hypermutation. The development of V-region-mutant B cells and the selections of high-avidity-autoantigen-reactive antibodies producing B cells by autoantigens from them, again, can lead to the development and propagation of autoimmune diseases such as lupus erythematosus or chronic inflammatory rheumatoid arthritis by the autoantibody BcR-expressing B cells and their secreted autoantibodies.
16376013 CNS demyelination in autoimmune diseases. 2006 Mar Autoimmune diseases represent a diverse group of disorders that have generally of unknown etiology and poorly understood pathogenesis. They may be organ-specific or systemic, giving rise to overlapping syndromes; more than one autoimmune disease may occur in the same patient. Numerous case reports have documented that multiple sclerosis (MS) may be present concurrently with other autoimmune diseases, most commonly rheumatoid arthritis, autoimmune thyroid disease, type I diabetes mellitus and pernicious anemia. Case reports of disseminated encephalomyelitis (DEM) coincidental with other autoimmune diseases are rare. Many of systemic autoimmune diseases cause central nervous system (CNS) demyelination and are frequently then diagnosed as MS, whereas they often are instances of DEM, the result of vascular, granulomatous or postinfectious manifestations. We have reviewed 15 patients with autoimmune diseases and CNS demyelination in order to determine the nature of the demyelinating process.
16218473 Pulmonary arterial hypertension associated to connective tissue diseases. 2005 Pulmonary arterial hypertension is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue diseases, and to a lesser extent, rheumatoid arthritis, dermatopolymyositis and primary Sjögren's syndrome. In these patients, pulmonary hypertension may occur in association with left heart disease, interstitial fibrosis or as a result of a isolated pulmonary arteriopathy. The incidence of pulmonary arterial hypertension in the limited form of systemic sclerosis is about 10%. The pathophysiologic mechanisms leading to pulmonary arterial hypertension remain unknown. Symptoms and clinical presentation are very similar to idiopathic pulmonary arterial hypertension but mortality was confirmed to be higher. Echocardiography is the reference investigation for the detection of pulmonary arterial hypertension but the results should be confirmed by right heart catheterization. Treatment appears more complex as compared to idiopathic pulmonary arterial hypertension. Intravenous epoprostenol therapy has been shown to be effective in a special trail. Also, the endothelin receptor antagonists bosentan and sitaxentan, the phosphodyesterase-type-5 sildenafil and subcutaneous treprostinil have shown favourable results.
16288807 Microcytosis in agnogenic myeloid metaplasia: prevalence and clinical correlates. 2006 Jun Microcytosis is a characteristic laboratory feature for both iron deficiency anemia and thalassemia. It is also infrequently seen in "anemia of chronic disease" that accompanies a spectrum of chronic conditions including rheumatoid arthritis, polymyalgia rheumatica, diabetes mellitus, connective tissue disease, and protracted infection. In addition, there is a well established but pathogenetically obscure association of microcytosis with Hodgkin's lymphoma, Castleman's disease, and renal cell carcinoma. In the current study, we show that microcytosis is a frequent laboratory feature in agnogenic myeloid metaplasia and investigate its clinical relevance in the particular setting.
16134776 A case of erythema nodosum and serositis associated with myelodysplastic syndrome. 2005 Jun Myelodysplastic syndrome (MDS) is a heterogenous group of stem cell disorders usually characterized by progressive refractory cytopenias, which could progress to acute myeloid leukemia. MDS may be associated with a wide spectrum of skin lesions, including neoplastic cell infiltration, Sweet's syndrome, pyoderma gangrenosum, erythema elevatum diutinum, vasculitis, and panniculitis. However, erythema nodosum is rarely associated with MDS. Unusual rheumatologic manifestations in patients with MDS also have been reported, which range from asymptomatic serological abnormalities to classic connective tissue disorders such as Sjögren's syndrome, relapsing polychondritis, systemic lupus erythematosus, rheumatoid arthritis and mixed connective tissue disease. However, concurrent erythema nodosum and serositis has rarely been reported. We describe a case of MDS with erythema nodosum and immune-mediated pericardial effusion in a 34-year-old woman.
15989099 [Secondary bladder amyloidosis with severe recurrent hematuria: transurethral Mickuliz pro 2005 May OBJECTIVES: Primary localized amyloidosis of the urinary bladder generally has a benign course. On the contrary, secondary amyloidosis, a consequence of systemic amyloidosis, may have massive bleeding and produce complications such as bladder rupture or life-threatening hemodynamic problems requiring desperate hemostatic procedures such as hypogastric artery embolization or ligature, or cystectomy. We report one case in which hemostasis was achieved by a Mickulicz transurethral bladder tamponage. METHODS: 58 year old female with very aggressive rheumatoid arthritis and secondary renal amyloidosis under chronic hemodialysis presenting with severe hematuria after hip replacement. An inflamed bladder was found, the biopsy of which showed edema in all layers with blood vessel walls enlarged by amiloyd deposits. After several unsuccessful transurethral hemostatic procedures, intravesical formalin irrigation was carried out together with a Mikulicz type gauze packaging after urethral dilation. The gauze was withdrawn three days later without bleeding recurrence; however she presented subsequent neurological impairment and finally died 14 days after the last urological procedure. CONCLUSIONS: Transurethral packaging of the urinary bladder in a woman with massive hematuria is a hemostatic option that we recommend to be used before other more dramatic or invasive options are chosen.
17045197 Glucocorticoid action and the development of selective glucocorticoid receptor ligands. 2006 Glucocorticoids are important endocrine regulators of a wide range of physiological systems ranging from respiratory development, immune function to responses to stress. Glucocorticoids in cells activate the cytoplasmic glucocorticoid receptor (GR) that dimerizes, translocates to the nucleus and functions as a ligand-dependent transcriptional regulator. Synthetic glucocorticoids such as dexamethasone and prednisolone have for decades been the cornerstone for the clinical treatment of inflammatory diseases, such as rheumatoid arthritis and asthma, and in some lymphoid cancers, yet its prolonged use has undesirable side effects such as obesity, diabetes, immune suppression and osteoporosis. Detailed knowledge on the mechanism of GR action has led to the development of novel selective glucocorticoid receptor modulators (SGRMs) that show promise of being efficacious for specific treatments of disease but with fewer side effects. SGRMs promote specific recruitment of transcriptional co-regulators that elicit specific gene responses and show promise of greater efficacy and specificity in treatment of inflammatory diseases and type-2 diabetes.
16913666 [Complement activation and inflammation]. 2006 Jul The complement system not only plays an important role in the defense system, but also contributes to the amplification of inflammation if activated in excess or inappropriately controlled. Complement activation through one of three pathways is tightly controlled by various regulators of complement activation (RCA) which are constitutively expressed on various cells in order to restrict excessive activation. Complement activation may generate polypeptides, so-called anaphylatoxins, and membrane attack complex (MAC) with large molecular mass. Anaphylatoxins (C3a, C4a, and C5a) produced by activation of the complement is considered to bridge innate and acquired immunity. Considering that C5a is more potent than C3a, but the serum concentration of C3 is 10 times higher than that of C5, the overall effects of C3a may be comparative with those of C5a. Since both anaphylatoxins are considered to exert their actions through rhodopsin-typed receptors, their receptor antagonists are targets for the discovery of anti-inflammatory and immune-modulating drugs. Complement activation may be related to the pathophysiology of various refractory disorders including ARDS, asthma, septic syndrome, SLE, rheumatoid arthritis, ischemia-reperfusion injury, and psoriasis etc. Pharmacological manipulation of the complement system may consist of various strategies including (1) inhibitors of complement activation at various levels, (2) receptor antagonists of anaphylatoxins, C3a and C5a, and (3) inhibitors of C5a including monoclonal antibody. Candidate agents concerning the above-mentioned manipulations have being produced and some are now in progress toward clinical trials in patients with certain diseases.
16835707 The role of leukotrienes in the pathophysiology of inflammatory disorders: is there a case 2006 Mar Leukotrienes (LTs), a family of lipid mediators, play a key role in the pathogenesis of inflammation. They are synthesized in the leucocytes from arachidonic acid (AA) via the actions of 5-lipoxygenase (5-LO). LTs are classified into two classes: LTB(4) and cysteinyl LTs (CysLTs). LTB(4) is one of the most potent chemoattractant mediators of inflammation. It exerts its actions through a seven transmembrane-spaning G protein receptors, LTB4 R-1 and LTB4 R-2. CysLTs (LTC(4), LTD(4), and LTE(4)) are potent bronchoconstrictors that play an important role in asthma. They induce their actions through G protein coupled receptors, CysLT R-1 and CysLT R-2. LTs are involved in the pathogenesis of inflammatory disorders specially asthma, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Therefore, LTs modifiers, LTs inhibitors or antagonists, represent important therapeutic advance in the management of inflammatory diseases. Zileuton, zafirlukast and montelukast are LTs modifiers that are approved to use for the treatment of inflammatory disorders.
16451303 Evidence for prescribing exercise as therapy in chronic disease. 2006 Feb Considerable knowledge has accumulated in recent decades concerning the significance of physical activity in the treatment of a number of diseases, including diseases that do not primarily manifest as disorders of the locomotive apparatus. In this review we present the evidence for prescribing exercise therapy in the treatment of metabolic syndrome-related disorders (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, obesity), heart and pulmonary diseases (chronic obstructive pulmonary disease, coronary heart disease, chronic heart failure, intermittent claudication), muscle, bone and joint diseases (osteoarthritis, rheumatoid arthritis, osteoporosis, fibromyalgia, chronic fatigue syndrome) and cancer, depression, asthma and type 1 diabetes. For each disease, we review the effect of exercise therapy on disease pathogenesis, on symptoms specific to the diagnosis, on physical fitness or strength and on quality of life. The possible mechanisms of action are briefly examined and the principles for prescribing exercise therapy are discussed, focusing on the type and amount of exercise and possible contraindications.
16413964 Multiple sclerosis: postlinkage genetics. 2006 Mar Because of the relative failure of linkage analysis in multiple sclerosis, despite the investigation of more than 700 affected relative pairs, we have applied four alternative strategies to identify genes that confer susceptibility to the disease. First, we have reported two clusters of MS patients from isolated populations where 19 and 13 patients, respectively, could be shown to have common ancestry tracing back several centuries. Three and five haplotypes, respectively, were shown to be shared by affected individuals, however, these haplotypes were extended and the statistical evidence modest. Second, we have recently reported the results of a two-stage candidate gene analysis of 66 selected genes, mostly of immune function. The IL-7 receptor alpha gene and LAG-3 both had three SNP markers associated with MS. Third, we recently identified the MHC class II transactivator gene in an animal model with inflammatory properties and later confirmed it to be of importance for MS, rheumatoid arthritis and acute myocardial infarction. Finally, in collaboration with the Serono Genetics Institute, we have completed a genome-wide screen with over 100,000 markers in three sets of 300 MS patients and 300 matched controls. Eighty genes showed evidence of importance in all three populations. These strategies appear to hold some promise of success where linkage analysis has proven less successful than anticipated.
16402217 Biological treatment in rheumatic diseases: results from a longitudinal surveillance: adve 2006 Aug The objective of this study was to assess the long-term safety and tolerability of biologicals in a clinical setting. Data on adverse events (AEs) have been collected over a 5-year period by means of detailed reports sent in to the National Register of Biological Treatment in Finland (ROB-FIN) and validated by information collected by the National Agency for Medicines. Three hundred and eight reports on AEs were filed, concerning a total of 248 patients; this corresponds to 17% of all patients in the ROB-FIN register who started biological treatments. Skin reactions and infections comprised 35 and 28% of the AEs, respectively. Some cases of tuberculosis and other infections, heart failure and demyelinating conditions were seen. Our work demonstrates no unexpected AEs in a Finnish patient cohort consisting of rheumatoid arthritis and spondylarthropathy patients, although many of them were treated with combination treatments in common use in Finland. Biological treatment appears safe in the hands of the Finnish rheumatologists.