RESUMEN
BACKGROUND: Benzodiazepines are used in pediatric patients with congenital heart disease (CHD) because of their mild hemodynamic depressant effects. A novel short-acting benzodiazepine, remimazolam, is expected to be suitable for these patients. We examined the characteristics of remimazolam anesthesia in pediatric patients with CHD undergoing cardiac catheterization. METHODS: This single-center retrospective study included pediatric patients undergoing cardiac catheterization for CHD. The primary outcome was the remimazolam dose for loss of consciousness. Secondary outcomes included the mean maintenance remimazolam dose, recovery time from anesthesia, predicted remimazolam concentration at emergence, decrease in blood pressure and heart rate, vasopressor administration during anesthesia, electroencephalogram index (bispectral index: BIS or patient state index: PSI), and life-threatening adverse events. RESULTS: Thirty-nine patients, aged 2 months to 16 years, were included. Thirty-three patients received a median [interquartile] midazolam dose of 0.10 [0.10-0.10] mg.kg-1 in the pre-anesthesia room. The remimazolam dose for loss of consciousness was 0.34 [0.26-0.45] mg.kg-1. The mean maintenance dose was 1.0 [0.8-1.4] mg.kg-1.h-1. The recovery time was 15 [12-17] min. The predicted remimazolam concentration at emergence was 0.4-1.2 µg.ml-1 in 3-6-year-old patients. Blood pressure and heart rate decreased by 30% in 15 and 6 patients, respectively. Vasopressors were administered as a bolus in 8 patients. The BIS or PSI did not fall ≤ 60 or ≤ 50, respectively, in 51% of patients before tracheal intubation. No life-threatening adverse events were reported. CONCLUSIONS: Remimazolam is a good alternative anesthetic agent for pediatric patients undergoing cardiac catheterization for CHD.
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Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule signal that is critical for NF-κB activation and is triggered through C-type lectin receptors (CLRs), which are pattern recognition receptors that recognize carbohydrate structures. Previous studies have reported that Cryptococcus neoformans, a fungal pathogen that causes meningoencephalitis in AIDS patients, is recognized through some CLRs, such as mannose receptors or DC-SIGN. However, the role of CARD9 in the host defense against cryptococcal infection remains to be elucidated. In the present study, we analyzed the role of CARD9 in the host defense against pulmonary infection with C. neoformans. CARD9 gene-disrupted (knockout [KO]) mice were highly susceptible to this infection, as shown by the reduced fungal clearance in the infected lungs of CARD9 KO mice, compared to that in wild-type (WT) mice. Gamma interferon (IFN-γ) production was strongly reduced in CARD9 KO mice during the innate-immunity phase of infection. Reduced IFN-γ synthesis was due to impaired accumulation of NK and memory phenotype T cells, which are major sources of IFN-γ innate-immunity-phase production; a reduction in the accumulation of these cells was correlated with reduced CCL4, CCL5, CXCL9, and CXCL10 synthesis. However, differentiation of Th17 cells, but not of Th1 cells, was impaired at the adaptive-immunity phase in CARD9 KO mice compared to WT mice, although there was no significant difference in the infection susceptibility between interleukin 17A (IL-17A) KO and WT mice. These results suggest that CARD9 KO mice are susceptible to C. neoformans infection probably due to the reduced accumulation of IFN-γ-expressing NK and memory phenotype T cells at the early stage of infection.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/fisiología , Interferón gamma/biosíntesis , Enfermedades Pulmonares Fúngicas/microbiología , Linfocitos T/inmunología , Animales , Quimiocinas/biosíntesis , Cryptococcus neoformans/genética , Modelos Animales de Enfermedad , Inmunidad Innata/fisiología , Enfermedades Pulmonares Fúngicas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células TH1/citología , Células Th17/citologíaRESUMEN
Because green tea polyphenols (GTPs) possess anti-inflammatory properties and are effective in inhibiting autoimmune diseases in experimental settings, we examined whether GTPs prevented the development of autoimmune thyroiditis in iodide-treated nonobese diabetic (NOD) mice, an animal model of Hashimoto's thyroiditis (HT). Mice were given 0.05% iodide water or iodide water supplemented with 0.2% GTPs for 8 weeks. GTPs administration led to an enhanced production of interleukin-10 by concanavalin A-stimulated splenocytes but did not interfere with thyroiditis development. Serum thyroxine levels were not influenced by GTPs. Our data suggest that administration of GTPs may not be an effective strategy for the prevention of HT.
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Modelos Animales de Enfermedad , Enfermedad de Hashimoto/prevención & control , Polifenoles/administración & dosificación , Té/química , Animales , Femenino , Enfermedad de Hashimoto/inducido químicamente , Enfermedad de Hashimoto/inmunología , Humanos , Yoduros/administración & dosificación , Masculino , Ratones , Ratones Endogámicos NOD , Tiroiditis Autoinmune/inducido químicamente , Tiroiditis Autoinmune/inmunología , Tiroiditis Autoinmune/prevención & controlRESUMEN
Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis in immunocompromised patients. Recently, we reported that Toll-like receptor 9 (TLR9) is involved in host defense against C. neoformans: specifically, it detects the pathogen's DNA. In the present study, we aimed to elucidate the mechanisms underlying TLR9-mediated activation of innate immune responses by using the URA5 gene, which encodes a virulent component of this fungal pathogen. A PCR-amplified 345-bp URA5 gene fragment induced interleukin-12 p40 (IL-12p40) production by bone marrow-derived dendritic cells (BM-DCs) in a TLR9-dependent manner. Similar activity was detected in the 5' 129-bp DNA fragment of URA5 and in a synthesized oligodeoxynucleotide (ODN) with the same sequence. Shorter ODN fragments, which contained GTCGGT or GACGAT but had only 24 or 21 bases, induced IL-12p40 production and CD40 expression by BM-DCs, but this activity vanished when the CG sequence was replaced by GC or when a phosphorothioate modification was introduced. IL-12p40 production caused by active ODN was strikingly enhanced by treatment with DOTAP, a cationic lipid that increases the uptake of DNA by BM-DCs, though DOTAP failed to induce IL-12p40 production by inactive ODN and did not affect the activity of an ODN-containing canonical CpG motif. There was no apparent difference in intracellular trafficking between active and inactive ODNs. Finally, an extremely high dose of inactive ODN suppressed IL-12p40 production by BM-DCs that had been stimulated with active ODN. These results suggest that the C. neoformans URA5 gene activates BM-DCs through a TLR9-mediated signaling pathway, using a mechanism possibly independent of the canonical CpG motif.
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Cryptococcus neoformans/genética , Cryptococcus neoformans/metabolismo , Células Dendríticas/fisiología , Macrófagos/fisiología , Orotato Fosforribosiltransferasa/metabolismo , Receptor Toll-Like 9/metabolismo , Animales , ADN de Hongos/inmunología , Ácidos Grasos Monoinsaturados , Regulación Fúngica de la Expresión Génica , Subunidad p40 de la Interleucina-12/metabolismo , Ratones , Ratones Noqueados , Orotato Fosforribosiltransferasa/genética , Fosfatos , Compuestos de Amonio Cuaternario , Receptor Toll-Like 9/genéticaRESUMEN
Hashimoto's thyroiditis, a common organ-specific autoimmune disease, is multifactorial in which both genetic susceptibility and environmental factors including infection play a critical role in its pathogenesis. Viral infection activates both the innate and adaptive immunity and is implicated as a trigger of Hashimoto's thyroiditis. Candidate viruses include hepatitis C virus and human parvovirus B19. Viral components, which are recognized by innate receptors including Toll-like receptors (TLRs), are detected in thyroid tissues and sera of patients with Hashimoto's thyroiditis. While conflicting results have been obtained regarding the role of TLRs in autoimmune diseases, our preliminary study suggested a contribution of TLR2 and dectin-1 in combination, TLR4, or TLR7 to the production of anti-thyroglobulin antibody in nonobese diabetic mice, a mouse model of Hashimoto's thyroiditis. Despite interesting circumstantial evidence, however, whether viral infection and innate receptors are involved in the development of Hashimoto's thyroiditis remains largely unclear. In this review, we summarize our knowledge regarding the role of viral infection and innate receptors in the etiology of Hashimoto's thyroiditis.
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Enfermedad de Hashimoto/complicaciones , Enfermedad de Hashimoto/virología , Inmunidad Innata/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Virosis/complicaciones , Animales , Enfermedad de Hashimoto/inmunología , Humanos , Modelos Biológicos , Receptores Toll-Like/inmunología , Virosis/inmunologíaRESUMEN
We examined whether a synthetic retinoid Am80 prevented the development of autoimmune thyroiditis in iodide-treated nonobese diabetic mice, an animal model of Hashimoto's thyroiditis (HT). Am80 (0, 0.1 or 1 mg/kg/day) was orally administered in feed during the 8-week iodide treatment. While iodide ingestion effectively induced thyroiditis, Am80 administration failed to interfere with thyroiditis development and serum anti-thyroglobulin antibody levels regardless of the dose of the retinoid. Splenic T cell numbers, splenocyte proliferation and interferon-γ production were decreased in the Am80-treated mice. Our data suggest that Am80 is not a candidate for use in the prevention of HT.
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Benzoatos/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/inmunología , Tetrahidronaftalenos/metabolismo , Tiroiditis Autoinmune , Administración Oral , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Benzoatos/administración & dosificación , Diabetes Mellitus Tipo 1/metabolismo , Interacciones Farmacológicas , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Recuento de Linfocitos , Ratones , Ratones Endogámicos NOD , Retinoides/administración & dosificación , Retinoides/metabolismo , Bazo/inmunología , Linfocitos T/inmunología , Tetrahidronaftalenos/administración & dosificación , Tiroiditis Autoinmune/inducido químicamente , Tiroiditis Autoinmune/metabolismo , Tiroiditis Autoinmune/prevención & controlRESUMEN
FTY720 is an immunomodulator that alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. This compound has been shown to be effective in suppressing autoimmune diseases in experimental and clinical settings. In the present study, we tested whether FTY720 prevented autoimmune thyroiditis in iodide-treated non-obese diabetic (NOD) mice, a model of Hashimoto's thyroiditis (HT) in humans. Mice were given 0.05% iodide water for 8 weeks, and this treatment effectively induced thyroiditis. Iodide-treated mice were injected intraperitoneally with either saline or FTY720 during the iodide treatment. FTY720 clearly suppressed the development of thyroiditis and reduced serum anti-thyroglobulin antibody levels. The number of circulating lymphocytes and spleen cells including CD4(+) T cells, CD8(+) T cells, and CD4(+)Foxp3(+) T cells was decreased in FTY720-treated mice. Our results indicate that FTY720 has immunomodulatory effects on iodide-induced autoimmune thyroiditis in NOD mice and may be a potential candidate for use in the prevention of HT.
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Glicoles de Propileno/uso terapéutico , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Esfingosina/análogos & derivados , Tiroiditis Autoinmune/prevención & control , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Citocinas/sangre , Femenino , Clorhidrato de Fingolimod , Citometría de Flujo , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/sangre , Yoduros , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos NOD , Esfingosina/uso terapéutico , Tiroiditis Autoinmune/inducido químicamenteRESUMEN
Viral infection is implicated as a cause of autoimmune diseases. Whereas its role in Hashimoto's thyroiditis (HT) remains undefined, recent studies suggested a link between human parvovirus B19 (B19) infection and HT. We tested such possibility by using B19 nonstructural protein 1 (NS1) transgenic C57BL/6 mice, which harbor nonpermissive genetic background (H-2(b)). Mice were immunized with either thyroglobulin (Tg) or saline. No thyroiditis developed in saline-treated mice and Tg-immunized males regardless of the presence or absence of NS1. In contrast, thyroiditis was induced by Tg immunization in 25% of transgenic females, but not in wild-type females. However, the thyroiditis incidence in the former did not differ significantly from that of the latter. In addition, intrathyroidal T-cell receptor gene expression was not augmented in Tg-immunized transgenic females. Immunization with Tg led to a comparable increase in serum anti-Tg antibody levels in the wild-type and transgenic mice. Our results indicate that the introduction of B19 NS1 gene into C57BL/6 mice is insufficient to promote the development of autoimmune thyroiditis. Further studies are required, however, before concluding that B19 infection is not involved in HT induction.