RESUMEN
BACKGROUND: Gout affects nearly 2 % of the population and is associated with repeated painful flares of arthritis. Preventive urate-lowering therapy is widely available, but only one third of patients receive adequate treatment. Lack of knowledge among healthcare professionals and patients within primary healthcare are implicated as partial explanations for this undertreatment. Nurse-led care has proved to be an effective model when treating patients with gout, but there is a need for more knowledge about factors that can be expected to influence the future implementation of such care. The aim of this study was to describe factors influencing existing gout care in primary healthcare and the conditions for a future implementation of nurse-led gout care based on national treatment recommendations. METHODS: In this qualitative study, focus group discussions with 56 nurses and physicians and individual interviews with eight managers were conducted at nine primary healthcare units in central Sweden. A deductive qualitative content analysis based on the main constructs of the framework Integrated Promoting Action on Research Implementation in Health Services was followed by an inductive analysis within the frames of the main constructs: innovation, recipients and context. RESULTS: Gout-related contacts with primary healthcare was described as being patient initiated, diagnostics was in some respects complex and nurse-led care was experienced as a favourable primary healthcare model in general (innovation). Gout was seen as a low-priority condition with acute flares and there was inadequate knowledge of gout, including preventive treatment (recipients). Primary healthcare was perceived as having a holistic but fragmented responsibility for gout care, recommendations against keeping waiting lists complicated follow-up appointments and a need for motivation and support when introducing new practices was emphasised (context). CONCLUSION: In this study, investigating the perspective of professionals, several factors were found to influence existing gout care. It will be crucial to target these factors in the development of a future implementation strategy.
Asunto(s)
Gota , Rol de la Enfermera , Gota/diagnóstico , Supresores de la Gota/uso terapéutico , Humanos , Atención Primaria de Salud , Investigación CualitativaRESUMEN
Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.
Asunto(s)
Artritis Reumatoide/enzimología , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Tirosina Quinasa 3 Similar a fms/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Empalme Alternativo/efectos de los fármacos , Empalme Alternativo/genética , Animales , Artritis Reumatoide/patología , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Masculino , Proteínas de la Membrana/farmacología , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , ARN Interferente Pequeño/metabolismo , Proteínas Represoras/genética , Transducción de Señal/efectos de los fármacos , Bazo/efectos de los fármacos , Bazo/metabolismo , Survivin , Regulación hacia Arriba/efectos de los fármacos , Adulto Joven , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
TKs are intracellular signaling molecules essential for cell homeostasis. Inhibition of TKs is used in treatment of malignancies and diabetes mellitus. The present study evaluated the role of Flt3 in antigen-induced arthritis. Mice were immunized with mBSA, and arthritis was induced by an i.a. injection of mBSA. Treatment with the Flt3 inhibitor sunitinib was started together with mBSA immunization or together with the induction of arthritis. The mBSA-injected joints were evaluated morphologically for signs of synovitis and bone/cartilage destruction. Markers of bone metabolism and antibody responses were measured by ELISA. Maturation of DCs in the bone marrow and spleen was evaluated by flow cytometry. Sunitinib treatment reduced the intensity of synovitis and the incidence of bone destruction. The reduction in bone destruction was seen when the treatment was started at the time of immunization or at the time of arthritis induction. The antiarthritic effect was achieved by inhibition of DCs, reduction of antibody production, and bone metabolism. Inhibition of Flt3 is a potent antiarthritic mechanism reducing antigen presentation, synovial inflammation, and bone resorption. Down-regulation of TKs may be a useful tool in the treatment of human RA.
Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Antineoplásicos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/enzimología , Células Dendríticas/enzimología , Indoles/farmacología , Pirroles/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Presentación de Antígeno/inmunología , Artritis Experimental/inmunología , Artritis Experimental/patología , Autoanticuerpos/inmunología , Huesos/enzimología , Huesos/inmunología , Huesos/patología , Cartílago/enzimología , Cartílago/inmunología , Cartílago/patología , Células Dendríticas/inmunología , Células Dendríticas/patología , Humanos , Articulaciones/enzimología , Articulaciones/inmunología , Articulaciones/patología , Ratones , Ratones Endogámicos BALB C , Sunitinib , Sinovitis/enzimología , Sinovitis/inmunología , Sinovitis/patología , Tirosina Quinasa 3 Similar a fms/inmunología , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
BACKGROUND: One of the hallmarks of rheumatoid arthritis (RA) is hyperplasia and inflammation of the synovial tissue being characterized by in situ occurrence of highly differentiated leukocytes. Fms-like tyrosine kinase 3 (Flt3) has a crucial role in hematopoiesis, regulation of cell proliferation, differentiation and apoptosis. Typically, Flt3 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand (Flt3-L). The highly differentiated cellular pattern in the synovium of the RA patients made us hypothesize that Flt3-L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis. METHODOLOGY/PRINCIPAL FINDINGS: To investigate occurrence of Flt3-L in RA we have measured its levels in matched serum and synovial fluid samples from 130 patients and 107 controls. To analyse the pro-inflammatory role of Flt3-L, we continuously overexpressed this protein locally in healthy mouse joints using homologous B-cell line transfected with Flt3-L gene. Additionally, recombinant Flt3-L was instillated intra-articularly in combination with peptidoglycans, a Toll Like Receptor 2-ligand with stong arthritogenic properties. Our results show significantly higher levels of Flt3-L in the synovial fluid as compared to serum levels in RA subjects (p = 0.0001). In addition, RA synovial fluid levels of Flt-3-L were significantly higher than these obtained from synovial fluids originating from non-inflammatory joint diseases (p = 0.022). Intra-articular administration of B-cell line transfected with Flt3-L gene resulted in highly erosive arthritis while inoculation of the same B-cell line without hyperexpression of Flt3-L did not induce erosivity and only in a minority of cases caused synovial proliferation! Flt3-ligand potentiated peptidoglycan induced arthritis as compared to mice injected with peptidoglycan alone (p<0.05). CONCLUSIONS/SIGNIFICANCE: Our findings indicate that Flt3-L is strongly expressed at the site of inflammation in human RA. It exerts both pro-inflammatory and tissue destructive properties once in the joint cavity. Owing to these properties, treatment attempts to neutralize this molecule should be considered in RA.