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ID PMID Title PublicationDate abstract
16574519 High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chr 2006 Aug Glucocorticoid (GC)-induced osteoporosis mostly affects trabecular bone of vertebrae. Only 30% of vertebral fractures are symptomatic, yet both clinical and radiological vertebral fractures have been associated with increased mortality and morbidity. The aims of this cross-sectional, outpatient-based study were to measure the prevalence of asymptomatic vertebral fractures in a large sample of post-menopausal women given GCs for different diseases; to compare prevalence of asymptomatic vertebral fractures according to disease, GC treatment and major risk factors; and to assess the quality of life in GC users with and without asymptomatic vertebral fractures. 551 patients referring to 39 centers as outpatients for their programmed follow-up and satisfying the inclusion criteria were included in the analysis. Each patient underwent structured medical interview (including dose and duration of GC therapy, major risk factors for osteoporosis, the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO) and a back function score questionnaire), thoraco-lumbar radiographs and subsequent morphometry; for 253 and 437 patients, respectively, lumbar spine bone mineral density (BMD) assessed by dual energy X-ray absorptiometry and calcaneal bone stiffness assessed by quantitative ultrasonometry were available. The prevalence of asymptomatic vertebral fractures resulted >37%, with >14% of patients having two or more asymptomatic vertebral fractures and was much higher than that found in epidemiological studies on healthy women. Distribution of asymptomatic vertebral fractures along the spine showed a bimodal pattern, with two peaks at T7 and T11. The prevalence of asymptomatic vertebral fractures clearly increased with age. Differences in prevalence among diseases were evidenced. When controlled for age, GC cumulative dose, duration of therapy and personal history of fractures, the adjusted prevalences were 30.77% for systemic lupus erythematosus, 33.78% for rheumatoid arthritis, 37.78% for asthma/chronic obstructive pulmonary disease, 43.20% for polymyalgia rheumatica and 43.36% for diseases grouped as "other vasculitides/connective tissue diseases". No significant association was found with GC cumulative dose and duration of therapy. Established risk factors for osteoporosis (except for age, years since menopause and personal history of fractures), lumbar spine BMD, calcaneal stiffness and QUALEFFO score were not associated with number and severity of asymptomatic vertebral fractures. Underlying disease is likely to contribute to the risk of fracture, but disease by itself could not be dissected from GC regimen. Vertebral fractures should be looked for carefully in all post-menopausal women receiving long-term systemic GCs since they can be asymptomatic and are scarcely predictable.
16525725 p38MAPK mediates IL-1-induced down-regulation of aggrecan gene expression in human chondro 2006 Apr The pleiotropic cytokine interleukin 1 (IL-1) is considered to be the principal inducer of mediators of cartilage degradation in both, osteoarthritis (OA) and rheumatoid arthritis (RA). IL-1 activates numerous signaling pathways involved in cartilage destruction and dedifferentiation of chondrocytes. In this study, we analyzed expression and functional effects of IL-1 in human chondrocytes. We found an IL-1-induced reduction in the expression of the cartilage specific proteoglycan aggrecan as an indicator for the IL-1-mediated dedifferentiation of chondrocytes. To block the IL-1-induced signaling pathways specifically, we incubated human chondrocytes and cartilage explants with IL-1 in the presence of different signal transduction inhibitors and analyzed their effect on aggrecan mRNA expression and IL-6 secretion. IL-6 has been found to act synergistically in the IL-1-induced suppression of the proteoglycan synthesis in chondrocytes. Our results led to the identification of p38MAPK and/or PI3K/JNK as being crucial for IL-1-induced IL-6 secretion by chondrocytes. IL-1-induced down-regulation of aggrecan expression was found to be mediated by p38MAPK and/or ERK1/2. The identification and characterization of these signaling pathways will enable us to develop new modulation strategies for therapeutic use in inflammatory joint diseases.
16142846 D-hormone and the immune system. 2005 Sep D-hormone [1,25(OH)2 D3] is an important immune system regulator that has been shown to inhibit development of autoimmune diseases including experimental inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes. Paradoxically, other immune mediated diseases (experimental asthma) and immunity to infectious organisms were not found to be affected by D-hormone treatment. The effectiveness of D-hormone treatment of autoimmune diseases is due to inhibition of the development and function of Th1 cells and the induction of other Th cells including Th2 cells. We report results of microarray analysis of colons from D-hormone treated mice with experimental IBD. Two hundred thirty-nine genes were inhibited and 298 genes were upregulated in the colon by D-hormone treatment of mice with IBD. Of interest was the D-hormone mediated inhibition of 3 tumor necrosis factor-alpha (TNF-alpha, lipopolysaccharide-induced TNF-alpha factor, and TNF receptor) related genes in the colon. It is likely that the effectiveness of D-hormone treatment of experimental autoimmunity is due in part to the inhibition of the TNF family of genes. D-hormone is a selective regulator of the immune system, and the outcome of D-hormone treatment depends on the nature (infectious disease, asthma, autoimmune disease, etc.) of the immune response.
16112121 Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced RO 2006 Apr Pathological hypoxia plays an important role in many diseases, such as atherosclerosis, cancer, and rheumatoid arthritis. The aim of the present study was to examine the effects of different statins on hypoxia-induced endothelial cell signalling. Human umbilical cord vein endothelial cells (HUVEC) were treated with NaCN (CN, 2.5 mmol/l) to simulate a transient hypoxia. The CN-induced increase of endothelial cell numbers was significantly (n = 10, p < 0.01) reduced by the Ca(2+) chelator BAPTA (10 micromol/l), or the reactive oxygen species (ROS) scavenger N-acetylcysteine (ACC, 1 mmol/l), or the NAD(P)H-oxidase inhibitor diphenyleneiodonium (DPI, 5 micromol/l). In detail, cell numbers were (in percentage of control): 163.24 (CN), 90.06 (CN+ACC), 92.06 (CN+DPI). Intracellular-Ca(2+) and -ROS, analysed by fluorescence imaging, were significantly increased by CN. Interestingly, the CN-induced increase of ROS was in part Ca(2+)-dependent, whereas the Ca(2+) increase was not ROS-dependent. Simvastatin (5 micromol/l), fluvastatin (2.5 micromol/l), and cerivastatin (0.1 micromol/l) all reduced CN-induced proliferation, ROS generation and Ca(2+) increase. Cell viability was not reduced by the statins and the antiproliferative effect was completely reversed by mevalonate (500 micromol/l). In conclusion our study demonstrates that statins block hypoxia-associated endothelial proliferation by preventing the increase of Ca(2+) and ROS.
15776286 Mechanistic insight into osteoclast differentiation in osteoimmunology. 2005 Mar Recently a close relationship between the immune and skeletal systems or the interdisciplinary field called osteoimmunology has attracted much attention due to the observations that bone destruction is caused by an abnormal activation of the immune system in rheumatoid arthritis, and that mice lacking immunomodulatory molecules often exhibit an unexpected bone phenotype. Osteoclasts are cells of monocyte/macrophage origin that degrade the bone matrix. They are among the key players in the control of bone metabolism in health and disease. Receptor activator of NF-kappaB ligand (RANKL), a tumor necrosis factor (TNF) family cytokine, induces the differentiation of osteoclasts in the presence of macrophage-colony stimulating factor. RANKL activates TRAF6, c-Fos, and calcium signaling pathways, all of which are indispensable for the induction and activation of nuclear factor of activated T cells (NFAT) c1, the master transcription factor for osteoclastogenesis. The autoamplification of NFATc1 gene results in the efficient induction of osteoclast-specific genes. An AP-1 transcription factor complex containing c-Fos plays a crucial role in these processes, although results in conditional knockout mice show that Jun family members have a redundant role. The immunoreceptor tyrosine-based activation motif (ITAM) is an important signaling component for a number of receptors in the immune system including T-cell, B-cell, NK-cell, and Fc receptors, but its contribution to the skeletal system remains unclarified. In search for the calcium-mobilizing mechanism during osteoclastogenesis we determined that multiple immunoglobulinlike receptors associated with ITAM-harboring adaptors, Fc receptor common gamma chain (FcRgamma), and DNAX-activating protein (DAP) 12, are essential for osteoclastogenesis. In osteoclast precursor cells FcRgamma-associated receptors include osteoclast-associated receptor and paired immunoglobulinlike receptor A, while triggering receptor expressed in myeloid cells 2 and signal-regulatory protein beta1 preferentially associate with DAP12. In cooperation with RANKL these receptors activate phospholipase Cgamma and calcium signaling essential for the induction of NFATc1 through ITAM phosphorylation. Thus we have established the importance of the ITAM-mediated costimulatory signals in RANKL-induced osteoclast differentiation, which is analogous to the role of costimulatory signals in the immune system. Here we summarize recent advances in the study of signaling mechanism of osteoclast differentiation in the context of osteoimmunology.
16819265 [A case in which the subject was affected by Listeia meningoencephalitis during administra 2006 Jun The subject was a 22-year-old woman who developed high fever and arthralgias and eruptions in the extremities around June 2005. She sought medical advice at a nearby dermatology clinic, where hepatic dysfunction was noted on blood testing. The patient was thus hospitalized the next day. Although CRP levels were significantly high, no sign of infection was observed and bone marrow cell differentiation was normal. Adult onset Still's disease was diagnosed based on the observation of persistent high fever >39 degrees C, eruptions, increased leukocytes, pharyngeal pain, splenomegaly, hepatic dysfunction, negative autoantibody results from blood testing, and high serum ferritin levels. Administration of prednisolone 30 mg/day was initiated, but proved ineffective. Steroid pulse therapy was conducted, and the subject was transferred to our medical facility for continued treatment. Attempts were made to control the disease using combined steroid and cyclosporine administration; but exacerbation of high serum ferritin levels and hepatic dysfunctions were observed, so a second course of steroid pulse therapy was conducted. Symptoms improved temporarily, but steroid levels were difficult to reduce. Cyclosporine was therefore replaced by methotrexate, and administration of infliximab was initiated. In the course of treatment, administration of a sulfamethoxazole/trimethoprim combination was initiated, but was discontinued due to suspicion of drug-induced hepatic injury. A second administration of infliximab was conducted in late August, and rapid improvements in clinical symptoms and abnormal test values was observed. However, high fever and headache developed suddenly in early September. Based on the results of spinal fluid testing, blood and spinal fluid cultures and MRI of the head, Listeria meningoencephalitis was diagnosed. Diplopia and impaired consciousness occurred during the disease course, and formation of a brain abscess was observed on imaging. However, symptoms were controlled by long-term combination administration of ampicillin and gentamicin. Administration of infliximab was discontinued for treatment of adult onset Still's disease, and steroid levels were reduced following double-membrane filtration plasma exchange. On follow-up, no relapse of symptoms or abnormalities in blood test values were observed, so the subject was discharged from our medical facility in December 2005. In treatment for rheumatic diseases, a dramatic improvement in treatment results for pathologies displaying tolerance against conventional treatments has been acquired with the development of biological drugs. However, opportunistic infections represent a serious problem, and appropriate preventative measures are required. The present report describes a case in which the subject was affected by Listeria meningoencephalitis during administration of infliximab for steroid-dependent adult Still's disease. Since listeriosis is one of the complications, along with tuberculosis, that warrants precautionary measures, this case is reported and discussed.
16178873 Cross-recognition between histones and La/SSB may account for anti-DNA reactivity in SLE p 2005 Oct Antibodies to La/SSB are detected in sera of patients with primary Sjogren's syndrome (pSS) and systemic lupus erythematosus (SLE). The vast majority of anti-La/SSB positive sera contain antibodies directed towards a linear B-cell epitope of La/SSB spanning the sequence 349-364aa (pep349-364). The aim of this study was to evaluate the fluctuation of antibody levels to major B-cell epitopes of La/SSB over time and investigate for their possible crossreactions. Sequential sera from 15 SLE and 15 pSS patients, followed from 3 to 10 years were obtained. All patients with SLE were positive for anti-Ro/SSA, anti-La/SSB and anti-dsDNA antibodies and patients with pSS were positive for anti-Ro/SSA and anti-La/SSB antibodies. Sera from 30 patients with SLE without anti-La/SSB antibodies and 30 healthy individuals served as disease and negative control respectivelly. All sera tested for the presence of anti-pep349-364 antibodies, using a specific ELISA. Specific anti-pep349-364 IgG was purified from sera of SLE patients and evaluated for cross reactivity against dsDNA and histones. In all SLE sera the levels of anti-pep349-364 antibodies varied in time and fluctuated in parallel with anti dsDNA antibodies. Anti-pep349-364 IgG purified from 7 SLE patients. Five out of 7 were found to react with calf thymus DNA in ELISA. All purified (7/7) anti-pep349-364 IgG preparations reacted with histone H1 and failed to produce a positive immunofluorescence pattern in Crithidia luciliae anti-dsDNA assay which lacks histones. Competative inhibition experiments demonstrated that histone H1 could inhibit completely the binding of anti-pep349-364 IgG to pep349-364 while pep349-364 inhibited by 70% the binding of anti-pep349-364 IgG to histone H1. These findings indicate that a subgroup of SLE patients possess cross-reacting anti-histone H1 antibodies and anti-pep349-364 antibodies, which can be faulty considered as anti-dsDNA reactivity in regular ELISA techniques.
17009014 Activation of MKK4 (SEK1), JNK, and c-Jun in labial salivary infiltrating T cells in patie 2007 Feb We wanted to determine via immunohistochemistry, whether or not c-Jun NH2-terminal kinase (JNK) cascade is activated in labial salivary infiltrating T cells in patients with Sjögren's syndrome (SS). Six patients with primary SS were selected for this study. Phosphorylation of mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) (SEK1), JNK, and c-Jun in salivary infiltrating T cells was studied using immunohistochemistry assay, including mirror section technique. Phosphorylated forms of MKK4, JNK, and c-Jun were detected in salivary infiltrating mononuclear cells. Expression of phosphorylated JNK was found in both CD4+ T cells and CD8+ T cells. Moreover, co-expression of phosphorylated JNK and c-Jun was demonstrated in the mirror sections. The results of this study suggest that the JNK cascade is activated in salivary infiltrating CD4+ T cells and CD8+ T cells in SS patients, which appears to contribute to the inflammatory salivary microenvironment of SS.
16972617 [A case of systemic amyloidosis treated by chemotherapy with autologous peripheral blood s 2006 Aug A 67-year-old woman was admitted to our hospital because of breathlessness. Systemic amyloidosis had been diagnosed 5 years previously. Her chest X-ray film showed multiple nodules in both lung fields. Chest computed tomography (CT) revealed some of the nodules had calcifications. Bronchoscopy demonstrated amyloid deposits in the bronchial walls. The serum titer of anti-SS-A antibody was high. Results of both the Schirmer Test and the Rose-Bengal Test were positive. The final diagnosis was systemic amyloidosis with Sjögren's syndrome. She was treated by chemotherapy using high dose melphalan with autologous peripheral blood stem cell transplantation (PBSCT). It was obvious that her chest X-ray film findings and bronchoscopic findings had improved 9 months after high dose chemotherapy with PBSCT. The disappearance of M protein and improvement of thirst, a symptom of Sjögren's syndrome, were also observed.
15184196 Tumour necrosis factor alpha blocking agents in refractory adult Still's disease: an obser 2005 Feb BACKGROUND: Consensus is lacking on treatment for corticosteroid resistant adult onset Still's disease (ASD). OBJECTIVE: To assess anti-TNFalpha efficacy and tolerance in refractory ASD. METHODS: All departments of rheumatology and internal medicine in France were contacted by mail to identify cases of refractory ASD for which anti-TNFalpha had been used. Medical information was collected using a standardised questionnaire. RESULTS: Of 20 patients with mean age 40.7 years (range 18-74) at treatment start and mean disease duration 8.5 years (range 2-21), the clinical expression of ASD was predominantly systemic in five patients and polyarticular in 15. Response to corticosteroids and methotrexate had been considered inadequate in all patients. Infliximab was used to treat 15 patients, and etanercept used for 10; five had received both drugs consecutively. Steroids were concurrently used in 18 patients and an immunosuppressant in 17. At a mean (SD) follow up of 13 (14) months, complete remission had occurred in five cases (of 25 treatment sequences): one receiving etanercept and four infliximab. Partial response was observed in 16 cases (seven etanercept and nine infliximab). Treatment failed in four cases (two with each anti-TNFalpha). At the last visit, anti-TNFalpha therapy was discontinued in 17 cases, 11 times because of lack (or loss) of efficacy, four times because of a side effect, and twice for other reasons. CONCLUSION: Anti-TNFalpha therapy may be helpful for some patients with refractory ASD. However, most patients achieve only partial remission. Additional information is thus needed to evaluate more precisely the risk-benefit ratio of this treatment.
16751222 IL-12 overexpression in mice as a model for Sjögren lung disease. 2006 Oct Interleukin-12 (IL-12), a Th1 proinflammatory cytokine, is reported to be increased in Sjögren syndrome. To evaluate the effects of local Th1/Th2 deregulation, we generated a transgenic mouse model that overexpresses IL-12 in the lungs. IL-12 transgenic mice developed bronchial and alveolar abnormalities strikingly similar to those found in the lungs of Sjögren patients. Pathologically, lung abnormalities began at approximately 4 mo of age and were characterized by lymphocytic infiltrates around the bronchi, intraluminal periodic acid Schiff-positive debris, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages. Functionally, these abnormalities translated into decreased mucociliary clearance (P<0.05 vs. wild-type littermates) and increased oxidative stress (P<0.01). The pathological and functional abnormalities were accompanied by significant changes in lung natural killer (NK) cells. The number of NK cells was fourfold higher in IL-12 transgenic than wild-type lungs (20% of all lymphoid cells vs. 5%) during the first month of life. NK cells then decreased within a narrow window of time (from 30 to 50 days of age), reaching a nadir of approximately 2% on day 50, and remained at these low levels thereafter. This new mouse model highlights the role of IL-12 in the initiation of Sjögren syndrome.
16370267 Tumor necrosis factor alpha inhibitors and methotrexate: implications for deployed personn 2005 Dec Rheumatic diseases such as rheumatoid and psoriatic arthritis are often diagnosed in younger age groups and are, therefore, likely to be encountered in active-duty military populations. These patients are increasingly being treated with disease modifying anti-rheumatic drugs (DMARDs) and biologic agents such as tumor necrosis factor alpha (TNF-alpha) inhibitors. While these classes of drugs have revolutionized the treatment of rheumatic diseases, they are also associated with serious potential adverse effects. At present, there are no published guidelines for the routine monitoring of laboratory parameters in patients receiving anti-TNF therapy. Currently, no official consensus among military physicians exists regarding duty and geographic limitations for patients receiving these types of therapy. Major adverse effects of these agents are reviewed in this article. A survey of U.S. Air Force, Army, and Navy rheumatologists was performed. The results of laboratory monitoring and operational deployment recommendations are reported. The majority of U.S. military rheumatologists do not recommend deployment of patients while taking methotrexate or TNF-alpha inhibitors.
16868974 Evaluation of the genetic association of the PTPN22 R620W polymorphism in familial and spo 2006 Aug OBJECTIVE: The R620W (1858C-->T) polymorphism in PTPN22 has been implicated in type 1 diabetes mellitus, rheumatoid arthritis, Graves' disease, Hashimoto thyroiditis, autoimmune thyroid disease, and systemic lupus erythematosus (SLE). The aim of this study was to evaluate this polymorphism in patients with familial SLE and in those with sporadic SLE. METHODS: A total of 4,981 DNA samples were genotyped (from 1,680 SLE patients, 1,834 family members, and 1,467 controls). Both population-based case-control and family-based association designs were used for the analyses. RESULTS: In the European American familial SLE cohort, the minor 1858T allele was more common in randomly selected patients compared with controls (chi2= 5.61, P = 0.018, odds ratio [OR] 1.46, 95% confidence interval [95% CI] 1.07-1.99). The heterozygous C/T genotype was also more common in these European American patients compared with controls (OR 1.63, 95% CI 1.15-2.30). Family-based association tests showed preferential transmission of the 1858T allele to affected offspring (chi2 = 5.87, P = 0.015). In contrast, the frequency of the 1858T minor allele was not significantly increased in the European American patients with sporadic SLE compared with controls, nor did these patients have preferential transmission of the 1858T allele. Indeed, the difference in the 1858T allele frequency between patients with familial SLE and those with sporadic SLE was measurable (allelic chi2= 4.22, P = 0.04, OR 1.51, 95% CI 1.02-2.24). Our data also showed that among patients with SLE, the 1858T allele was separately associated with type 1 diabetes mellitus and with autoimmune thyroid disease, confirming the findings of other investigators. CONCLUSION: The 1858T allele of PTPN22 is associated with familial SLE but not with sporadic SLE in European Americans, thereby potentially explaining previous contradictory reports.
16686369 Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine abso 2006 Jan Sulfasalazine is used in the treatment of ulcerative colitis, Crohn's disease, and rheumatoid arthritis. When administered orally, sulfasalazine is poorly absorbed with an estimated bioavailability of 3-12%. Recent studies using the T-cell line (CEM) have shown that sulfasalazine is a substrate for the ATP-binding cassette (ABC) efflux pump ABCG2. ABCG2 is known to efflux a number of xenobiotics and appears to be a key determinant of efficacy and toxicity of ABCG2 substrates. To date, there has not been any systematic study on the mechanisms involved in the transport of sulfasalazine in vivo. Accordingly, we investigated whether Bcrp (abcg2) is involved in the disposition of sulfasalazine. After oral administration of 20 mg/kg sulfasalazine, the area under the plasma concentration (AUC) time profile in Bcrp1 (abcg2)-/- knockout (KO) mice was approximately 111-fold higher than that in FVB wild-type (WT) mice. After intravenous administration of 5 mg/kg sulfasalazine, the AUC in Bcrp1 (abcg2)-/- KO mice was approximately 13-fold higher than that in WT mice. Moreover, treatment of WT mice with a single oral dose of gefitinib (Iressa; 50 mg/kg), a known inhibitor of Bcrp, given 2 h prior to administering a single oral dose of sulfasalazine (20 mg/kg), resulted in a 13-fold increase in the AUC of sulfasalazine compared to the AUC in vehicle-treated mice. Since gefitinib is also an inhibitor of P-glycoprotein (P-gp), the impact of P-gp on sulfasalazine absorption in vivo was also examined. The sulfasalazine AUC in mdr1a-/- KO versus WT mice did not differ significantly after either an oral (20 mg/kg) or an intravenous dose (5 mg/kg). We conclude that Bcrp (abcg2) is an important determinant for the oral bioavailability and the elimination of sulfasalazine in the mouse, and that sulfasalazine has the potential to be utilized as a specific in vivo probe of Bcrp (abcg2).
16170686 Inflammatory dilated cardiomyopathy (DCMI). 2005 Sep Cardiomyopathies are heart muscle diseases, which have been defined by their central hemodynamics and macropathology and divided in five major forms: dilated (DCM), hypertrophic (HCM), restrictive (RCM), right ventricular (RVCM), and nonclassifiable cardiomyopathies (NCCM). Furthermore, the most recent WHO/WHF definition also comprises, among the specific cardiomyopathies, inflammatory cardiomyopathy as a distinct entity, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy has been defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm(2)), the term viral cardiomyopathy or viral persistence in DCM should be applied according to the WHF Task Force recommendations. Within the German heart failure net it is the authors' working hypothesis, that DCM shares genetic risk factors with other diseases of presumed autoimmune etiology and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases including DCM. Therefore, the authors' primary goal is to acquire epidemiologic data of patients with DCM regarding an infectious and inflammatory etiology of the disease. Circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. In addition, autoimmune reactions have been described in many studies, indicating them as an important etiologic factor. Nevertheless, data on the proportion of patients, in whom both mechanisms play a role are still missing.A pivotal role for autoimmunity in a substantial proportion of patients with DCM is supported by the presence of organ-specific autoantibodies, inflammatory infiltrates and pro-inflammatory cytotoxic cytokines. Furthermore, familial occurrence of DCM has been described in about 20-30% of cases, with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. A similar pattern of humoral and cellular immune dysregulation has been described in other autoimmune diseases. There is considerable evidence that genetic factors play an important role in the pathogenesis of DCM, either as contributors to the susceptibility to environmental factors or as determinants of functional and structural changes that characterize the phenotypic expression of the disease.Yet, it is not known whether the susceptibility to immunologically mediated myocardial damage reflects the presence of genetic risk factors shared by other autoimmune diseases. Preliminary investigations suggest, that this is the case, because the frequency of autoimmune disorders other than DCM was higher in first-degree relatives of the subjects with DCM including juvenile diabetes, rheumatoid arthritis, thyroiditis, psoriasis, and asthma. The nature of the genetic risk is undetermined and probably involves genes in the major histocompatibility (MHC) locus as well as other susceptibility loci. Therefore, the authors started their investigation with the search for MHC class 2 DQ polymorphisms in the peripheral blood of patients with DCM in parallel to the search for new interesting susceptibility loci by the use of the microarray analysis regarding genes responsible for inflammatory and autoimmune diseases. By this approach a new insight in the familial clustering of other autoimmune diseases in patients with DCM and in genetic predisposition can be expected.
16133077 Can povidone-iodine solution be used safely in a spinal surgery? 2006 Jun Intra-operative incidental contamination of surgical wounds is not rare. Povidone-iodine solution can be used to disinfect surgical wounds. Although povidone-iodine is a good broad-spectrum disinfecting agent, it has occasionally been reported to have a negative effect on wound healing and bone union. Therefore, its safety in a spinal surgery is unclear. A prospective, single-blinded, randomized study was accordingly conducted to evaluate the safety of povidone-iodine solution in spinal surgeries. Ascertained herein was the effect of wound irrigation with diluted povidone-iodine solution on wound healing, infection rate, fusion status and clinical outcome of spinal surgeries. MATERIALS AND METHODS: From January 2002 to August 2003, 244 consecutive cases undergoing primary instrumented lumbosacral posterolateral fusion due to degenerative spinal disorder with segmental instability had been collected and randomly divided into two groups: the study group (120 cases, 212 fusion levels) and the control group (124 cases, 223 fusion levels). Excluded were those patients with a prior spinal surgery, spinal trauma, malignant tumor, infectious spondylitis, rheumatoid arthritis, ankylosing spondylitis, metabolic bone disease, skeletal immaturity or with an immunosuppressive treatment. In the former group, wounds were irrigated with 0.35% povidone-iodine solution followed by normal saline solution just before the bone-grafting and instrumentation procedure. However, only with normal saline solution in the latter. All the operations were done by the same surgeon with a standard technique. All the patients were treated in the same postoperative fashion as well. Later on, wound healing, infection rate, spinal bone fusion and clinical outcome were evaluated in both groups. RESULTS: A significant improvement of back and leg pain scores, modified Japanese Orthopedic Association function scores (JOA) and ambulatory capacity have been observed in both groups. One hundred and seven patients in the study group and one hundred and nine in the control group achieved solid union. There was no infection in the study group but six deep infections in the control group. Wound dehiscence was noted in one group 1 and two group 2 patients. A subsequent statistical analysis revealed higher infection rate in the control group (P<0.05), but no significant difference in fusion rate, wound healing, improvement of pain score, function score and ambulatory capacity between the two groups. CONCLUSION: Diluted povidone-iodine solution can be used safely in spinal surgeries, and it will not influence wound healing, bone union and clinical outcome.
15674908 Methotrexate for induction of remission in refractory Crohn's disease. 2005 Jan 25 BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, approximately 20% of patients who respond relapse when steroids are withdrawn and become steroid dependent (Binder 1985). Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine/6MP therapy. The evidence for its effectiveness has not been subjected to a systematic review. OBJECTIVES: To conduct a systematic review of the evidence for effectiveness of methotrexate for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. SEARCH STRATEGY: A computer-assisted search of MEDLINE and EMBASE for relevant studies published in English, French, Spanish, Italian and German between 1966 and July 2004. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. The Cochrane Controlled Trials Register and the IBD Review Group Specialized Trials Register were also searched. SELECTION CRITERIA: Randomized controlled trials involving patients of age > 17 years with refractory Crohn's disease defined by conventional clinical, radiological and endoscopic criteria, which was categorized as being active (Crohn's disease activity index >150). OUTCOME MEASURES: The outcome measure was the rate of induction of remission and complete withdrawal from steroids in the treatment and control groups after > 16 weeks of treatment. A secondary outcome was induction of remission with reduction in steroid dose of at least 50%. Selection of trials: The results of the searches above were reviewed independently by two observers and relevant studies selected according to the predefined selection criteria. Any disagreement among reviewers was resolved by consensus. The same two reviewers assessed the methodological quality of each trial (details of randomization method, including whether intention-to-treat analysis was possible from the published data, number of patients lost to follow-up, and if a blinded outcome assessment was used). A standard data extraction form was used. Appropriateness of combining results: Trials were first reviewed to assess the clinical comparability of trial protocols and study populations. MAIN RESULTS: Five randomized trials were identified. The five studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to combine the data statistically. Three small studies which employed low doses of methotrexate orally showed no statistically significant difference between methotrexate and placebo/control medication treated patients. One small study which used a higher dose of intravenous/oral methotrexate showed no statistically significant difference between methotrexate and azathioprine. A larger study which employed a higher dose of methotrexate intramuscularly showed substantial benefit (number needed to treat, NNT=5). Adverse effects were more common with high dose intramuscular methotrexate therapy than with placebo. AUTHORS' CONCLUSIONS: There is evidence from a single large randomized trial on which to recommend the use of methotrexate 25 mg intramuscularly weekly for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Although adverse effects were more common than with placebo, they were not severe. There is no evidence on which to base a recommendation for use of lower dose oral methotrexate.
15817701 TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-opera 2005 Jul Tumor necrosis factor alpha (TNF-alpha) is a potent, pleiotrophic cytokine, which is proinflammatory but can also suppress T lymphocyte function. In chronic inflammatory disease such as rheumatoid arthritis, exposure of T cells to TNF-alpha alters their ability to mount a response by modulating the T cell receptor (TCR) signaling pathway, but the mechanisms involved remain obscure. Here, we investigated the specific role of TNF receptor 1 (TNFR1) signaling in the modulation of the TCR signaling pathway. We observed a down-regulation of the intracellular calcium ([Ca(2+)](i)) signal in Jurkat T cells after just 30 min exposure to TNF-alpha, and maximum suppression was reached after 3 h. This effect was transient, and signals returned to normal after 12 h. This depression of [Ca(2+)](i) was also observed in human CD4+ T lymphocytes. The change in Ca(2+) signal was related to a decrease in the plasma membrane Ca(2+) influx, which was apparent even when the TCR signal was bypassed using thapsigargin to induce a Ca(2+) influx. The role of TNF-alpha-induced activation of the sphingolipid cascade in this pathway was examined. The engagement of TNFR1 by TNF-alpha led to a time-dependent increase in acid sphingomyelinase (SMase; ASM) activity, corresponding with a decrease in cellular sphingomyelin. In parallel, there was an increase in cellular ceramide, which correlated directly with the decrease in the magnitude of the Ca(2+) response to phytohemagglutinin. Exogenous addition of SMase or ceramide mimicked the effects of TNFR1 signals on Ca(2+) responses in Jurkat T cells. Direct evidence for the activation of ASM in this pathway was provided by complete abrogation of the TNF-alpha-induced inhibition of the Ca(2+) influx in an ASM-deficient murine T cell line (OT-II(+/+)ASM(-/-)). This potent ability of TNF-alpha to rapidly modulate the TCR Ca(2+) signal via TNFR1-induced ASM activation can explain its suppressive effect on T cell function. This TNFR1 signaling pathway may play a role as an important regulator of T cell responses.
16565497 Type I interferon production by tertiary lymphoid tissue developing in response to 2,6,10, 2006 Apr Lymphoid neogenesis is associated with antibody-mediated autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. Although systemic lupus erythematosus is the prototypical B-cell-mediated autoimmune disease, the role of lymphoid neogenesis in its pathogenesis is unknown. Intraperitoneal injection of 2,6,10,14-tetramethyl-pentadecane (TMPD, pristane) or mineral oil causes lipogranuloma formation in mice, but only TMPD-treated mice develop lupus. We report that lipogranulomas are a form of lymphoid neogenesis. Immunoperoxidase staining of lipogranulomas revealed B cells, CD4(+) T cells, and dendritic cells and in some cases organization into T- and B-cell zones. Lipogranulomas also expressed the lymphoid chemokines CCL21, CCL19, CXCL13, CXCL12, and CCL22. Expression of the type I interferon (IFN-I)-inducible genes Mx1, IRF7, IP-10, and ISG-15 was greatly increased in TMPD- versus mineral oil-induced lipogranulomas. Dendritic cells from TMPD lipogranulomas underwent activation/maturation with high CD86 and interleukin-12 expression. Magnetic bead depletion of dendritic cells markedly diminished IFN-inducible gene (Mx1) expression. We conclude that TMPD-induced lupus is associated with the formation of ectopic lymphoid tissue containing activated dendritic cells producing IFN-I and interleukin-12. In view of the increased IFN-I production in systemic lupus erythematosus, these studies suggest that IFN-I from ectopic lymphoid tissue could play a role in the pathogenesis of experimental lupus in mice.
16542377 Increased expression and secretion of interleukin-6 in human parvovirus B19 non-structural 2006 Apr Human parvovirus B19 (B19) has been associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We have demonstrated previously that B19 non-structural protein (NS1) induced apoptosis through the mitochondria cell death pathway in COS-7 epithelial cells and that B19 NS1 may play a role in the pathogenesis of autoimmune diseases. In order to examine the expression profiles of cytokines and chemokines in B19 NS1 transfected COS-7 cells, we constructed the NS1 gene in the pEGFP-C1 vector named enhanced green fluorescence protein gene (EGFP)-NS1. COS-7 cells were transfected with EGFP or EGFP-NS1 plasmid. The expression profiles of cytokines and chemokines, including interleukin (IL)-1beta, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-related oncogene alpha (GROalpha), interferon gamma-inducible protein (IP)-10, stromal cell derived factor (SDF)-1, macrophage inflammatory protein (MIP)-1beta, monocyte chemoattractant protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES), Fractalkine, CX3CR1, CCR2, CCR5 and CCR11 were examined in COS-7 cells, EGFP and EGFP-NS1 transfected cells using enzyme-linked immunosorbent assay (ELISA) or reverse transcription-polymerase chain reaction (RT-PCR). Increased expression and levels of IL-6 were found in EGFP-NS1 transfected cells using RT-PCR and ELISA. There were no significant increases in the expression of IL-1beta, IL-8, IP-10, SDF-1, RANTES, Fractalkine, CX3CR-1, CCR2, CCR5, CCR11, TNF-alpha, GM-CSF and TGF-beta using RT-PCR. There were no significantly increased levels of IL-5, IL-10, TNF-alpha, TGF-beta, GROalpha, MIP-1beta and MCP-1 found by ELISA in this study. Our results show that increased expression and secretion of IL-6 in B19 NS1 transfected epithelial cells may play a role in the pathogenesis of autoimmune diseases.