RESUMEN
The aim of this study was to evaluate the in vitro steroid sensitivity as a predictor of clinical response to glucocorticoids in childhood idiopathic nephrotic syndrome (INS). Seventy-four patients (median age 4.33, interquartile range [IQR] 2.82-7.23; 63.5% male) were enrolled in a prospective multicenter study: in vitro steroid inhibition of patients' peripheral blood mononuclear cell proliferation was evaluated by [methyl-(3) H] thymidine incorporation assay at disease onset (T0) and after 4 weeks (T4) of treatment. Steroid dependence was associated with increased in vitro sensitivity at T4 assessed both as drug concentration inducing 50% of inhibition (IC50 ; odds ratio [OR] = 0.48, 95% confidence interval [CI] = 0.24-0.85; P = 0.0094) and maximum inhibition at the highest drug concentration (Imax ; OR = 1.13, 95% CI = 1.02-1.31; P = 0.017). IC50 > 4.4 nM and Imax < 92% at T4 were good predictors for optimal clinical response. These results suggest that this test may be useful for predicting the response to glucocorticoid therapy in pediatric INS.
Asunto(s)
Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Metilprednisolona/administración & dosificación , Metilprednisolona/farmacología , Síndrome Nefrótico/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Estudios Prospectivos , Recurrencia , Factores de TiempoRESUMEN
Glucocorticoids (GCs) exert their effects through regulation of gene expression after activation in the cytoplasm of the glucocorticoid receptor (GR) encoded by NR3C1 gene. A negative feedback mechanism resulting in GR autoregulation has been demonstrated through the binding of the activated receptor to intragenic sequences called GRE-like elements, contained in GR gene. The long noncoding RNA growth arrest-specific transcript 5 (GAS5) interacts with the activated GR suppressing its transcriptional activity. The aim of this study was to evaluate the possible role of GAS5 and NR3C1 gene expression in the antiproliferative effect of methylprednisolone in peripheral blood mononuclear cells and to correlate the expression with individual sensitivity to GCs. Subjects being poor responders to GCs presented higher levels of GAS5 and NR3C1 in comparison with good responders. We suggest that abnormal levels of GAS5 may alter GC effectiveness, probably interfering with the mechanism of GR autoregulation.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , ARN Largo no Codificante/biosíntesis , Receptores de Glucocorticoides/biosíntesis , Adulto , Proliferación Celular/efectos de los fármacos , Femenino , Glucocorticoides/genética , Glucocorticoides/metabolismo , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , ARN Largo no Codificante/genética , Receptores de Glucocorticoides/genética , Transcripción GenéticaRESUMEN
BACKGROUND AND OBJECTIVE: The aim of the present study was to determine the association between genotypes of the MDR1 gene, encoding P-glycoprotein, and gingival overgrowth in transplant patients treated with cyclosporine, and to evaluate the effect of periodontal treatment in these patients. MATERIAL AND METHODS: Fifty transplant patients receiving therapy with cyclosporine and suffering from gingival overgrowth were subjected to nonsurgical periodontal treatment and received oral hygiene instructions. Hyperplastic index, periodontal probing depths, bleeding and plaque scores were recorded at baseline and after 3 and 6 mo. Patients were dichotomized into two groups: those with a hyperplastic index of < 30% (minimal gingival overgrowth) and those with a hyperplastic index of > or = 30% (clinically significant gingival overgrowth). MDR1 C3435T and G2677T polymorphisms were evaluated in all patients and in 100 controls. RESULTS: At baseline, 32 patients (64%) had minimal gingival overgrowth and 18 patients (36%) had clinically significant gingival overgrowth. The mutated C3435T genotype was significantly more frequent in the second group (p < 0.019). The significant association between gingival overgrowth and the 3435TT genotype was confirmed by logistic regression analysis (p < 0.031). The differences in hyperplastic index, observed at baseline between patients with the TT genotype and those with the CC/CT genotype disappeared in the second and third evaluation. The mean monthly change of the square root of the gingival overgrowth scores for all patients, assessed using linear models, was significantly different from baseline (-0.17 points per month, p < 0.00001); and this was particularly evident in subjects with renal transplant (-1.62, p < 0.01). CONCLUSION: Aetiological periodontal and self-performed maintenance therapy is effective in reducing gingival overgrowth, particularly in subjects with the 3435TT genotype and in patients with renal transplant.