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OBJECTIVES: We examined the financial burden of osteoporosis in Austria. METHODS: We took both direct and indirect costs into consideration. Direct costs encompass medical costs such as expenses for pharmaceuticals, inpatient and outpatient medical care costs, as well as other medical services (e.g., occupational therapies). Non-medical direct costs include transportation costs and medical devices (e.g., wheel chairs or crutches). Indirect costs refer to costs of productivity losses due to absence of work. Moreover, we included costs for early retirement and opportunity costs of informal care provided by family members. While there exist similar studies for other countries, this is the first comprehensive study for Austria. For our analysis, we combined data of official statistics, expert estimates as well as unique patient surveys that are currently conducted in the course of an international osteoporotic fracture study in Austria. RESULTS: Our estimation of the total annual costs in the year 2008 imposed by osteoporosis in Austria is 707.4 million . The largest fraction of this amount is incurred by acute hospital treatment. Another significant figure, accounting for 29% of total costs, is the opportunity cost of informal care. CONCLUSIONS: The financial burden of osteoporosis in Austria is substantial. Economic evaluations of preventive and therapeutic interventions for the specific context of Austria are needed to inform health policy decision makers.
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Costos de la Atención en Salud/estadística & datos numéricos , Hospitalización/economía , Programas Nacionales de Salud/economía , Fracturas Osteoporóticas/economía , Atención al Paciente/economía , Atención Ambulatoria/economía , Austria , Cuidadores/economía , Costos y Análisis de Costo , Costos de los Medicamentos/estadística & datos numéricos , Femenino , Traumatismos del Antebrazo/economía , Traumatismos del Antebrazo/prevención & control , Política de Salud/economía , Fracturas de Cadera/economía , Fracturas de Cadera/prevención & control , Servicios de Atención de Salud a Domicilio/economía , Atención Domiciliaria de Salud/economía , Humanos , Fracturas del Húmero/economía , Fracturas del Húmero/prevención & control , Tiempo de Internación/economía , Masculino , Fracturas Osteoporóticas/prevención & control , Pensiones/estadística & datos numéricos , Fracturas de las Costillas/economía , Fracturas de las Costillas/prevención & control , Fracturas de la Columna Vertebral/economía , Fracturas de la Columna Vertebral/prevención & controlRESUMEN
OBJECTIVES: Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined. METHODS: To determine whether TNF directly triggers bone loss or requires IL1, human TNFalpha mice (hTNFtg) were crossed with mice lacking IL1alpha and IL1beta (IL1(-/-)hTNFtg). Systemic bone architecture was evaluated using CT scanning, static and dynamic bone histomorphometry and serum markers of bone metabolism. RESULTS: hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were thinner and decreased in numbers, resulting in increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice compared with wild-type mice. In contrast, IL1(-/-)hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL1 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice and the increased levels of RANKL in these mice. Structural parameters and osteoclast and osteoblast numbers were indistinguishable from wild-type mice. CONCLUSIONS: These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.
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Artritis Experimental/complicaciones , Artritis Reumatoide/complicaciones , Enfermedades Óseas Metabólicas/etiología , Interleucina-1/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Biomarcadores/sangre , Densidad Ósea/fisiología , Enfermedades Óseas Metabólicas/metabolismo , Enfermedades Óseas Metabólicas/patología , Enfermedades Óseas Metabólicas/fisiopatología , Resorción Ósea/fisiopatología , Tomografía con Microscopio Electrónico , Femenino , Interleucina-1/deficiencia , Ratones , Ratones Transgénicos , Osteoblastos/patología , Osteoclastos/patología , Tibia/ultraestructuraRESUMEN
OBJECTIVE: Churg-Strauss Syndrome (CSS) is characterized by excessive eosinophil accumulation in peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. The contribution of eosinophil-chemotactic cytokines (eotaxin family) to eosinophilia and disease activity in CSS is unknown. Thus, we compared serum levels of the eotaxin family members in CSS patients with healthy and disease controls. METHODS: Forty patients with CSS diagnosed according to ACR 1990 criteria, 30 healthy controls (HC) and 57 disease controls (28 asthma, 20 small vessel vasculitis, 9 hypereosinophilic syndrome) were studied. Clinical data were collected and serum levels of eotaxin-1, -2 and -3 were determined by ELISA. Further, immunohistochemistry was applied to identify eotaxin-3 expression in tissue biopsies from patients with CSS. RESULTS: In contrast to eotaxin-1 and -2, eotaxin-3 was highly elevated in serum samples of active CSS patients and correlated highly significantly with eosinophil counts, total immunoglobulin E (IgE) levels and acute-phase parameters. Moreover, eotaxin-3 was not elevated in other eosinophilic and vasculitic diseases. Immunohistochemical analysis revealed strong expression of eotaxin-3 in endothelial and inflammatory cells in affected tissues of active CSS patients. CONCLUSIONS: This study reveals the specific association of elevated eotaxin-3 expression with high disease activity and eosinophilia in CSS patients. Eotaxin-3 might thus be a pathogenic player, biomarker and potential therapeutic target in CSS.
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Quimiocinas CC/sangre , Síndrome de Churg-Strauss/sangre , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Biopsia , Quimiocina CCL11/sangre , Quimiocina CCL24/sangre , Quimiocina CCL26 , Quimiocinas CC/metabolismo , Síndrome de Churg-Strauss/metabolismo , Síndrome de Churg-Strauss/patología , Eosinofilia/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vasculitis/sangreRESUMEN
OBJECTIVE: Crescentic glomerulonephritis (crGN) is a frequent and life-threatening manifestation of antineutrophil cytoplasmatic antibody-associated vasculitis. Up-regulation of proinflammatory cytokines contributes to renal damage by activation of p38 mitogen-activated protein kinases (MAPKs). However, it is unclear which of the four p38MAPK isoforms are expressed, activated and hence of major importance in crGN. METHODS: Kidney biopsies of patients with antineutrophil cytoplasmatic antibody-positive crGN and control samples were investigated for the expression and phosphorylation of p38MAPK isoforms and downstream target kinase MAPKAP2 by immunohistochemistry. Expression and functional activation of p38MAPK isoforms by TNF was also assessed in a human podocyte cell line by reverse transcription-polymerase chain reaction, immunoblotting and kinase array. RESULTS: Strong expression of p38MAPKalpha, beta and gamma isoforms was found in glomerular podocytes and crescents. Infiltrating leucocytes showed predominant p38MAPKalpha expression. Activation of p38MAPK and its downstream mediator MAPKAP2 was found in crGN confined to glomerular podocytes, crescents and inflammatory infiltrates. Interestingly, corticosteroid treatment before kidney biopsy diminished p38MAPK activation in crGN. Activated p38MAPK co-localised with alpha, beta and gamma isoforms in podocytes and crescents, while leucocytes showed mainly p38MAPKalpha activation. In a human podocyte cell line mRNA and protein of all four p38MAPK isoforms was expressed but only p38MAPKalpha was activated upon challenge with TNF. CONCLUSIONS: This study shows selective p38MAPK isoform expression and activation in crGN. Podocytes and podocyte-induce crescent formation is the main source of p38MAPK activation in crGN. TNF is a potent and selective activator of the alpha-isoform in podocytes, which therefore appears as a main contributor to proinflammatory signalling in the glomerulum of crGN.
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Glomerulonefritis Membranoproliferativa/enzimología , Glomérulos Renales/enzimología , Proteínas Quinasas p38 Activadas por Mitógenos/análisis , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Biopsia , Western Blotting/métodos , Estudios de Casos y Controles , Células Cultivadas , Activación Enzimática , Glomerulonefritis Membranoproliferativa/inmunología , Granulomatosis con Poliangitis/inmunología , Granulomatosis con Poliangitis/metabolismo , Humanos , Inmunohistoquímica , Isoenzimas/análisis , Isoenzimas/metabolismo , Leucocitos/enzimología , Macrófagos/enzimología , Proteína Quinasa 14 Activada por Mitógenos/análisis , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Fosforilación , Podocitos/enzimología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no Paramétricas , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Density fluctuations resulting from spinodal decomposition in a nonequilibrium first-order chiral phase transition are explored. We show that such instabilities generate divergent fluctuations of conserved charges along the isothermal spinodal lines appearing in the coexistence region. Thus, divergent density fluctuations could be a signal not only for the critical end point but also for the first-order phase transition expected in strongly interacting matter. We also compute the mean-field critical exponent at the spinodal lines. Our analysis is performed in the mean-field approximation to the Nambu-Jona-Lasinio model formulated at finite temperature and density. However, our main conclusions are expected to be generic and model independent.
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Osteoporosis is a major clinical problem in rheumatoid arthritis. Patients with rheumatoid arthritis frequently not only present with juxta articular osteopenia and bone erosions but also with generalized axial and appendicular osteoporosis at sites distant from inflamed joints. The pathogenesis of bone loss in rheumatoid arthritis is multifactorial; disease activity certainly is a major determinant of bone mass. Further pathogenetic factors include effects of anti-inflammatory therapies (in particular glucocorticoids), reduced mobility, estrogen and/or androgen deficiency. Recently, receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG), a decoy receptor for receptor activator of nuclear factor kappa B ligand, were identified as central regulators of osteoclast recruitment and activation. Osteoprotegerin and receptor activator of nuclear factor kappa B ligand production is modulated by several cytokines, growth factors and hormones. In rheumatoid synovium both fibroblasts and activated T cells express receptor activator of nuclear factor kappa B ligand and thereby promote osteoclast recruitment and activation. Thus, osteoprotegerin and receptor activator of nuclear factor kappa B ligand appear to represent important molecular links between the immune system and bone metabolism in rheumatoid arthritis.
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Artritis Reumatoide/complicaciones , Artritis Reumatoide/fisiopatología , Osteoporosis/etiología , Osteoporosis/fisiopatología , Progresión de la Enfermedad , HumanosRESUMEN
For patients with severe forms of autoimmunity, including systemic lupus erythematosus (SLE), purging autoreactive T cells from the immune repertoire by transplanting autologous hematopoietic stem cells (ASCT) is a therapeutic option. We describe an 18-year-old woman with SLE who had been treated with corticosteroids, azathioprine, cyclophosphamide (CYC), and immunopheresis for 4 years, during which time mechanical ventilation for lupus pneumonitis had been repeatedly required. After the patient was conditioned by administration of CYC and antithymocyte globulin, a total of 8.87 x 10(6) purified CD34+ cells per kg of body weight was infused. Hematopoietic regeneration was observed within 9 days. Twenty-one months after ASCT, the patient continues to be in complete clinical remission, with no signs of SLE-related disease activity and without any immunosuppressive medications. Her pulmonary function has returned to normal. Although a longer followup is required for assessment of the durability of response, the patient's course indicates that ASCT may be a way to reinduce tolerance in patients with SLE.
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Trasplante de Células Madre Hematopoyéticas , Lupus Eritematoso Sistémico/terapia , Neumonía/terapia , Adolescente , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Neumonía/diagnóstico por imagen , Neumonía/etiología , Pruebas de Función Respiratoria , Tomografía Computarizada por Rayos X , Trasplante AutólogoRESUMEN
OBJECTIVE: To explore the effects of rheumatic diseases and glucocorticoids on bone mass a group of patients suffering from systemic lupus erythematosus (SLE, n=18) and rheumatoid arthritis (RA, n=22) were examined. DESIGN: We examined 40 patients and 48 controls with quantitative ultrasound (QUS) and dual-energy X-ray absorptiometry (DXA). RESULTS: QUS (broadband ultrasound attenuation, BUA; speed of sound, SOS) values were found to be significantly lower in patients than in controls ( P<0.001). QUS measurements were moderately correlated with DXA measurements (kappa score ( kappa) 0.28 at the lumbar spine, and 0.46 at the femoral neck). There were no significant relations between the dosage of glucocorticoids and QUS parameters. CONCLUSION: In patients suffering from inflammatory rheumatic diseases QUS values were significantly decreased. SOS but not BUA and DXA measurements reflected disease activity assessed by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). QUS reflects different aspects of bone status compared with DXA.
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Artritis Reumatoide/diagnóstico por imagen , Huesos/diagnóstico por imagen , Lupus Eritematoso Sistémico/diagnóstico por imagen , Absorciometría de Fotón , Adulto , Densidad Ósea , Calcáneo/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Cuello Femoral/diagnóstico por imagen , Glucocorticoides/metabolismo , Humanos , Vértebras Lumbares/diagnóstico por imagen , Premenopausia , UltrasonografíaRESUMEN
The Omega/Omega ratio originating from string decays is predicted to be larger than unity in proton-proton interactions at SPS energies ( E(lab) = 160 GeV). The antiomega dominance increases with decreasing beam energy. This surprising behavior is caused by the combinatorics of quark-antiquark production in small and low-mass strings. Since this behavior is not found in a statistical description of hadron production in proton-proton collisions, it may serve as a key observable to probe the hadronization mechanism in such collisions.
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We derive the quantum kinetic equation for a pure gluon plasma, applying the background field and closed-time-path method. The derivation is more general and transparent than earlier works. A term in the equation is found which, as in the classical case, corresponds to the color charge precession for partons moving in the gauge field.
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A kinetic master equation for multiplicity distributions is formulated for charged particles which are created or destroyed only in pairs due to the conservation of their Abelian charge. It allows one to study time evolution of the multiplicity distributions in a relativistic many-body system with arbitrary average particle multiplicities. It is shown to reproduce the equilibrium results for both canonical (rare particles) and grand canonical (abundant particles) systems. For canonical systems, the equilibrium multiplicity is much lower and the relaxation time is much shorter than the naive extrapolation from grand canonical results. Implications for chemical equilibration in heavy-ion collisions are also discussed.
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OBJECTIVE: To investigate the expression of the transcription factor Ets-1 in synovial tissue and cultured synovial fibroblasts from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to study the regulation of Ets-1 expression and activation in synovial fibroblasts by proinflammatory cytokines. METHODS: In situ expression of Ets-1 in synovial tissue from RA and OA patients was examined by double immunohistochemistry. The effects of interleukin-1 (IL-1) or tumor necrosis factor alpha (TNFalpha) on Ets-1 expression and activation (DNA binding) in cultured synovial fibroblasts were analyzed by Western blotting and DNA gel shift assay, respectively. In addition, the intracellular location of Ets-1 in synovial fibroblasts was determined by immunofluorescence. RESULTS: Pronounced expression of Ets-1 was detected in synovial tissues from all RA patients evaluated, particularly in the synovial lining layer and the sublining areas. Ets-1 was expressed by both fibroblasts and macrophages as well as by endothelial cells, while only a few T cells stained positive for Ets-1. In synovial specimens from OA patients, Ets-1 expression was much less frequently observed and was largely restricted to vascular cells. Ets-1 was expressed to a similar degree in cultured synovial fibroblasts from RA and OA patients, as demonstrated by reverse transcriptase-polymerase chain reaction and Western blotting. Both IL-1 and TNFalpha induced pronounced up-regulation of Ets-1 in synovial fibroblasts. Moreover, binding of Ets-1 to its specific DNA binding site was induced by both cytokines, although with different time courses. Immunofluorescence staining revealed a dominant nuclear localization of Ets-1 in IL-1- or TNFalpha-stimulated synovial fibroblasts. CONCLUSION: The overexpression of Ets-1 observed in RA synovial tissue appears to be caused by TNFalpha and IL-1, suggesting that Ets-1 may be an important factor in the cytokine-mediated inflammatory and destructive cascade characteristic of RA.
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Artritis Reumatoide/metabolismo , Proteínas Proto-Oncogénicas/biosíntesis , Membrana Sinovial/metabolismo , Factores de Transcripción/biosíntesis , Células Cultivadas , Fibroblastos/química , Fibroblastos/citología , Humanos , Interleucina-1/farmacología , Osteoartritis/metabolismo , Proteína Proto-Oncogénica c-ets-1 , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-ets , Factores de Transcripción/análisis , Factores de Transcripción/fisiología , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate whether stress- and mitogen-activated protein kinases (SAPK/MAPK), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, are significantly activated in rheumatoid arthritis (RA) synovial tissue compared with their activation in degenerative joint disease; to assess the localization of SAPK/MAPK activation in rheumatoid synovial tissue; and to search for the factors leading to stress kinase activation in human synovial cells. METHODS: Immunoblotting and immunohistology by antibodies specific for the activated forms of SAPK/MAPK were performed on synovial tissue samples from patients with RA and osteoarthritis (OA). In addition, untreated and cytokine-treated human synovial cells were assessed for SAPK/MAPK activation and downstream signaling by various techniques. RESULTS: ERK, JNK, and p38 MAPK activation were almost exclusively found in synovial tissue from RA, but not OA, patients. ERK activation was localized around synovial microvessels, JNK activation was localized around and within mononuclear cell infiltrates, and p38 MAPK activation was observed in the synovial lining layer and in synovial endothelial cells. Tumor necrosis factor alpha, interleukin-1 (IL-1), and IL-6 were the major inducers of ERK, JNK, and p38 MAPK activation in cultured human synovial cells. CONCLUSION: Signaling through SAPK/MAPK pathways is a typical feature of chronic synovitis in RA, but not in degenerative joint disease. SAPK/MAPK signaling is found at distinct sites in the synovial tissue, is induced by proinflammatory cytokines, and could lead to the design of highly targeted therapies.
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Artritis Reumatoide/enzimología , Artritis Reumatoide/patología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Membrana Sinovial/enzimología , Células Cultivadas , Citocinas/farmacología , Activación Enzimática/efectos de los fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos , Proteína Quinasa 3 Activada por Mitógenos , Osteoartritis/enzimología , Osteoartritis/patología , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
We compute the pressure of a finite-density quark-gluon plasma at zero temperature to leading order in hard-thermal-loop perturbation theory, which includes the fermionic excitations and Landau damping. The result is compared with the weak-coupling expansion for finite positive chemical potential &mgr; through order alpha(2)(s) and with a quasiparticle model with a mass depending on &mgr;.
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OBJECTIVE: To evaluate bone mineral density and biochemical parameters of bone metabolism in ambulatory premenopausal female patients with systemic lupus erythematosus (SLE). METHODS: 30 women who fulfilled the ARA criteria for the classification of SLE were studied. Lumbar and femoral bone mineral density was determined by dual energy x ray absorptiometry. Various laboratory parameters including serum calcium, serum phosphorus, alkaline phosphatase, bone specific isoform of alkaline phophatase, propeptide of type 1 procollagen, deoxypyridinoline excretion, telopeptide of type 1 collagen, serum creatinine, osteocalcin, parathyroid hormone, 25-OH vitamin D, testosterone, progesterone, estradiol, follicle stimulating hormone and luteinotropic hormone were measured. RESULTS: According to the WHO criteria 39% of all patients with SLE studied had normal bone mineral density, 46% had osteopenia and 15% had osteoporosis at the lumbar spine; at the femoral neck 38.5% had normal bone mineral density, 38.5% had osteopenia and 23% suffered from osteoporosis. Significantly lower osteocalcin levels were found in SLE patients. All other bone resorption and formation markers measured were not statistically different, but higher serum albumin corrected calcium and lower phosphorus values were found in the SLE group. Of all sex hormones tested lower testosterone and higher follicle stimulating hormone concentrations were seen in patients with SLE. CONCLUSION: A high incidence was found of osteopenia and osteoporosis in premenopausal patients with SLE. Bone diminution in SLE seems to be attributable, at least in part, to decreased bone formation in SLE patients.
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Densidad Ósea/fisiología , Huesos/metabolismo , Lupus Eritematoso Sistémico/fisiopatología , Adolescente , Adulto , Enfermedades Óseas Metabólicas/etiología , Femenino , Fémur/fisiopatología , Humanos , Vértebras Lumbares/fisiopatología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/metabolismo , Persona de Mediana Edad , Osteoporosis/etiología , Premenopausia/fisiologíaRESUMEN
OBJECTIVE: To investigate the expression of the stroma cell product stem cell factor (SCF) in synovial fibroblasts (SFB) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and to analyze the capacity of SFB to induce mast cell (MC) chemotaxis. METHODS: Synovial tissue was obtained from 29 patients with RA and 25 patients with OA. Tissue was dispersed by enzymatic digestion using collagenase. SFB were grown in serial passage and exposed to tumor necrosis factor alpha (TNFalpha) or control medium. Expression of SCF in cultured SFB was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunostaining. The ability of SFB (supernatants) to induce MC migration was analyzed using a double-chamber chemotaxis assay and the human mast cell line HMC-1. In situ expression of SCF in synovial tissue from patients with RA (n = 6) and OA (n = 6) was examined by double immunohistochemistry using antibodies against SCF and the fibroblast-specific antibody AS02. RESULTS: In both RA and OA, cultured SFB were found to express SCF messenger RNA, as assessed by RT-PCR. In addition, the SCF protein was detectable in cell lysates and supernatants of SFB by ELISA. Incubation of SFB with TNFalpha resulted in an increased expression and release of SCF. Recombinant human SCF (rHuSCF) and SFB supernatants induced significant migration of HMC-1 cells above control levels. In addition, exposure of SFB to TNFalpha led to an increased migration of HMC-1, and a blocking anti-SCF antibody inhibited the rHuSCF- and SFB-induced migration of HMC-1. In situ double immunostaining revealed expression of SCF in AS02-positive SFB in the synovium of patients with RA. CONCLUSION: Our results show that SFB (in RA and OA) express SCF and induce MC chemotaxis. Furthermore, TNFalpha was found to augment SCF expression in SFB. It is hypothesized that these cellular interactions play an important role in MC accumulation and related events in RA.
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Quimiotaxis/efectos de los fármacos , Mastocitos/citología , Factor de Células Madre/genética , Células Madre/inmunología , Membrana Sinovial/citología , Factor de Necrosis Tumoral alfa/farmacología , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Biopsia , Células Cultivadas , Quimiotaxis/inmunología , Ensayo de Inmunoadsorción Enzimática , Fibroblastos/citología , Fibroblastos/inmunología , Fibroblastos/metabolismo , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Humanos , Mastocitos/inmunología , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Solubilidad , Factor de Células Madre/análisis , Células Madre/citología , Células Madre/metabolismo , Membrana Sinovial/química , Membrana Sinovial/inmunologíaRESUMEN
Ticlopidine is increasingly used in the secondary prophylaxis in patients with arterial occlusive diseases. Neutropenia is a well known side effect of this drug. We report a case of a 73 year old woman who was admitted because of severe prolonged ticlopidine induced leucopenia. The past medical history included an immunocytoma of the IgM-kappa type diagnosed seven years ago with less than 10% infiltration of the bone marrow and a chronic hepatitis C. On admission the white cell count was 1000/microL. Ticlopidine was stopped. The white cell count did not increase within one week, thus filgastrim was applied on two consecutive days. The leucocyte count promptly increased to 6000/microL but consecutively dropped within the next fortnight again to levels below 500/microL forcing daily filgastrim application for another 9 days. Four months after the initiation of the therapy with filgastrim the patient had a white cell count of 4300/microL. We therefore conclude that in patients with a history of potentially bone marrow suppressing diseases the use of ticlopidine has to be carefully weighed against possible myelosuppressive effects.
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Arteriopatías Oclusivas/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucopenia/inducido químicamente , Inhibidores de Agregación Plaquetaria/efectos adversos , Ticlopidina/efectos adversos , Anciano , Arteriopatías Oclusivas/inmunología , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Femenino , Hepatitis C Crónica/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Inhibidores de Agregación Plaquetaria/administración & dosificación , Recurrencia , Factores de Riesgo , Ticlopidina/administración & dosificaciónRESUMEN
Heat shock proteins (hsp) have been repeatedly implicated to participate in the pathogenesis of rheumatoid arthritis (RA). Herein, we investigated the regulation of synovial hsp70 expression by analyzing the DNA-binding activity of heat shock transcription factor 1 (HSF1) as well as inducible hsp70 expression. Experiments were performed both on synovial tissue and on synovial fibroblast-like cells (SFC). Gel mobility shift analysis revealed increased HSF1 activation, and Western blotting and immunohistochemistry revealed increased hsp70 expression in RA synovial tissue, but not in synovial tissue derived from patients with osteoarthritis. Proinflammatory cytokines (TNF-alpha, IL-1alpha, IL-6), but not IFN-gamma or TGF-beta, induced activation of HSF1-DNA binding and hsp70 expression in cultivated SFC. Activation of HSF1 in SFC was accompanied by hyperphosphorylation and nuclear translocation of HSF1. Furthermore, shear stress also induced a complete heat shock response in cultivated synovial cells. In contrast, nonsteroidal antiinflammatory drugs triggered only an incomplete heat shock response, with HSF1 activation but not hsp70 induction, whereas steroids and immunosuppressive drugs did not affect the heat shock response at all. In summary, these data suggest that induction of hsp70 expression in rheumatoid synovial tissue is based on transcriptional activation of HSF1 due to the presence of proinflammatory cytokines (and possibly also shear stress).