RESUMEN
Kawasaki disease (KD) is a paediatric vasculitis whose pathogenesis remains unclear. Based on experimental studies using a mouse model for KD, we report here that proline-rich protein tyrosine kinase 2 (Pyk2) plays a critical role in the onset of KD-like murine vasculitis. The mouse model for KD was prepared by administrating a Candida albicans water-soluble fraction (CAWS). Unlike CAWS-treated WT mice, CAWS-treated Pyk2-Knockout (Pyk2-KO) mice did not develop apparent vasculitis. A sustained increase in MIG/CXCL9 and IP-10/CXCL10, both of which have potent angiostatic activity, was observed in CAWS-treated Pyk2-KO mice. CAWS-induced activation of STAT3, which negatively regulates the expression of these chemokines, was also attenuated in macrophages derived from Pyk2-KO mice. The present study suggests that defects in Pyk2 suppress KD-like experimental vasculitis, presumably through CXCL9- and CXCL10-dependent interference with neo-angiogenesis. Since Pyk2-KO mice show no life-threatening phenotype, Pyk2 may be a promising therapeutic molecular target for KD.
Asunto(s)
Quinasa 2 de Adhesión Focal/genética , Síndrome Mucocutáneo Linfonodular/metabolismo , Animales , Aorta/metabolismo , Candida albicans , Quimiocina CXCL10/sangre , Quimiocina CXCL9/sangre , Vasos Coronarios/metabolismo , Modelos Animales de Enfermedad , Macrófagos/metabolismo , Ratones Noqueados , Síndrome Mucocutáneo Linfonodular/sangre , Factor de Transcripción STAT3/metabolismo , Tenascina/metabolismoRESUMEN
BACKGROUND: Little is known about the platelet dynamics and the effect of antiplatelet therapy in Kawasaki disease (KD). The aim of this study was to clarify platelet activation dynamics in acute-phase KD patients by assaying platelet-derived microparticles (PDMPs). METHODS AND RESULTS: The PDMP level in 18 patients with acute KD was measured on ELISA. Of the 18 patients, 14 were receiving oral aspirin and i.v. immunoglobulin (IVIG) and 4, oral aspirin alone. Blood samples were drawn before, immediately after, and 10-14 days after IVIG infusion; thereafter, at 1, 2, and 3 months after the onset of disease. PDMP level before aspirin treatment was significantly higher in acute-phase KD patients than in the control subjects with common febrile diseases (P<0.01). In the acute-phase KD patients, IVIG significantly decreased PDMP level; the PDMP level was not lower on the similar day of KD in the patients who did not receive IVIG. Eight patients' PDMP level rebounded after aspirin was discontinued. CONCLUSIONS: Platelets are activated during acute-phase KD, which confirms the importance of antiplatelet therapy. In addition, platelet activation continues as long as 2 or 3 months after the acute phase, the time at which aspirin is commonly discontinued, and the timing of aspirin discontinuation should therefore be evaluated in each individual patient.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Plaquetas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Síndrome Mucocutáneo Linfonodular , Activación Plaquetaria/efectos de los fármacos , Plaquetas/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/patologíaRESUMEN
BACKGROUND: Anti-platelet therapy for Kawasaki disease (KD) is often done without monitoring drug efficacy. The aim of this study was to investigate the utility of whole-blood aggregometry to evaluate the efficacy of anti-platelet therapy for KD. METHODS: Of 37 late-phase KD patients included in the present study, 20 were prescribed anti-platelet drugs. Platelet-rich plasma (PRP) aggregation with collagen as the stimulus was measured using an optical aggregometer. The area under the curve of small and large size aggregations was calculated, and categorized into five classes: -2, -1, 0, 1, and 2. Whole-blood aggregation with collagen or adenosine 5'-diphosphate (ADP) as stimulus was evaluated using the platelet aggregation threshold index (PATI), which is the concentration of stimulus that induces a whole-blood aggregation rate of 50%. RESULTS: In both collagen- and ADP-induced aggregation, there was a negative correlation between PATI and class determination using the PRP technique (collagen, rs = -0.870, P < 0.0001; ADP, rs = -0.620, P < 0.0001). Moreover, the PATI in collagen- and ADP-induced aggregation was significantly higher in the anti-platelet drug therapy group than in the untreated group (collagen, P < 0.0001; ADP, P = 0.0002). The serum thromboxane B2 level in the anti-platelet drug therapy group was also significantly lower than that in the untreated group (P < 0.0001). PATI was significantly higher in those treated with thienopyridine drug combinations than those without drug therapy (P = 0.0036). CONCLUSIONS: Whole-blood aggregometry is useful for monitoring the efficacy of anti-platelet therapy for KD.
Asunto(s)
Plaquetas/efectos de los fármacos , Monitoreo de Drogas/estadística & datos numéricos , Síndrome Mucocutáneo Linfonodular/sangre , Inhibidores de Agregación Plaquetaria/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Agregación Plaquetaria/efectos de los fármacos , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Determining the nature of binding in grapheme-color synaesthesia has consequences for understanding the neural basis of synaesthesia and visual awareness in general. We evaluated type- and token-based letter-color binding using a synaesthetic version of the object-reviewing paradigm. Although mean response times failed to reveal any significant differences between synaesthetes and control participants, RT analyses with ex-Gaussian distributions revealed that the response facilitation in the synaesthesia group reflected type representations exclusively, while response facilitation in the control group, who learned letter-color associations, was dominated by token representations. Thus, letter-color associations in associator synaesthetes are type-based, and do not involve binding to object tokens, consistent with their subjective reports. Contrary to recent studies that failed to find differences between synaesthetes and non-synaesthetes with behavioral measures, response time distribution analyses indicate that color sensations in synaesthetes are not simply the extreme form of normal letter-color associations, and cannot be attributed to demand characteristics.