RESUMEN
BACKGROUND: Cortisol is produced in a circadian rhythm controlled by the hypothalamus-pituitary-adrenal axis, making it cumbersome to measure long-term cortisol exposure. Hair has proven to be a reliable matrix for long-term cortisol measurement in adults and can be used as diagnostic tool for (cyclic) Cushing's syndrome. The diagnostic applicability in children has not been studied, nor have the effects of development and hair care been evaluated in children. We aimed to establish reference ranges of hair cortisol concentrations (HCC) in healthy children and to evaluate the effects of age, gender, puberty and characteristics of hair care. METHODS: In 128 healthy children aged 4-14 years, HCC were measured in a small 3-cm hair lock from the back of the head. RESULTS: HCC increased with age (p = 0.04) up to age 10 years, with a mean of 5.0, 5.8, 6.8 and 8.5 pg/mg at age 4-5, 6-7, 8-9 and 10-14 years, respectively. Children aged 4-7 years had significantly lower HCC compared to healthy adults (p = 0.007). We did not find any influence of gender, puberty or hair care characteristics on hair cortisol. CONCLUSION: HCC can be reliably measured in childhood, and reference ranges increase with age. HCC in children are not dependent on hair care or hair characteristics.
Asunto(s)
Cabello/metabolismo , Hidrocortisona/metabolismo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Hidrocortisona/análisis , Masculino , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismoRESUMEN
To date, seven studies have provided evidence for an association between the gene encoding for myosin IXB (MYO9B) and celiac disease (CD), and inflammatory bowel diseases, including single nucleotide polymorphisms (SNPs) rs2305767, rs1457092, and rs2305764. We investigated whether MYO9B is associated with T1D. The three SNPs were genotyped in Dutch samples from 288 T1D patients and 1615 controls. The A allele of SNP rs2305767A>G showed some evidence of association with T1D (nominal p for genotype = 0.06; OR carrier = 1.51, 95% CI = 1.04-2.19), but not in British samples from 4301 case patients and 4706 controls (p = 0.53), or when the Dutch and UK data were pooled (N patients = 4582, N controls= 6224; Mantel-Hansel p = 0.83). Furthermore, the nonsynonymous rs1545620 C>A SNP that has been associated with the inflammatory bowel disease, showed no association with T1D in British case-control set (p = 0.57). We conclude that MYO9B might not be a strong determinant of T1D, although there was some association in our initial Dutch study. Further studies are needed to evaluate the role of MYO9B in T1D.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Miosinas/metabolismo , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Análisis Mutacional de ADN , Diabetes Mellitus Tipo 1/inmunología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Miosinas/genética , Miosinas/inmunología , Países Bajos , Polimorfismo de Nucleótido Simple , Reino UnidoRESUMEN
Previous studies have shown that enteroviral RNA can be detected in blood at the onset of type 1 diabetes (T1D). The infection may play a role in triggering T1D and genetic host factors may contribute to this process. We investigated (1) whether enterovirus is present at the onset of T1D in peripheral blood mononuclear cells (PBMC), plasma, throat, or stool, and (2) whether enteroviral presence is linked with HLA-DR type and/or polymorphisms in melanoma differentiation-associated gene 5 (MDA5) and 2'-5' oligoadenylate synthetase 1 (OAS1), factors of antiviral immunity. To this end, PBMC, plasma, throat, and stool samples from 10 T1D patients and 20 unrelated controls were tested for the presence of enteroviruses (RT-PCR), for HLA-DR type, and polymorphisms in MDA5 and OAS1. Enterovirus RNA was detected in PBMC of 4/10 T1D patients, but none of 20 controls. Plasma was positive in 2/10 T1D patients and none of 20 controls, suggesting that enteroviruses found at the onset of T1D are mainly present in PBMC. All throat samples from positive T1D patients were virus-negative and only 1 fecal sample was positive. The negative results for all throat and most stool samples argues against acute infection. Enterovirus presence was linked with HLA-DR4, but not with polymorphisms in MDA5 or OAS1.
Asunto(s)
Sangre/virología , Diabetes Mellitus Tipo 1/virología , Infecciones por Enterovirus/complicaciones , Infecciones por Enterovirus/virología , Enterovirus/aislamiento & purificación , Leucocitos Mononucleares/virología , ARN Viral/aislamiento & purificación , 2',5'-Oligoadenilato Sintetasa/genética , Adolescente , Niño , Preescolar , ARN Helicasas DEAD-box/genética , Enterovirus/genética , Heces/virología , Femenino , Antígenos HLA-DR/genética , Humanos , Helicasa Inducida por Interferón IFIH1 , Masculino , Faringe/virología , Plasma/virología , Polimorfismo Genético , ARN Viral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Cost-effectiveness of continuous subcutaneous insulin infusion (CSII) in children is reviewed in the context of possible improvement of percentage of hemoglobin A1c (HbA1c) and of other clinical benefits over multiple daily injections (MDI). Cost-effectiveness depends on clinical efficacy but reported clinical efficacy parameters may overlook definite benefits perceived by children and parents using CSII. There are few detailed reports on cost comparisons between CSII and MDI in adults, even less in children or adolescents. Review of direct extra costs for CSII over conventional treatment, including MDI, suggest that these may double, 5000-6000 EUR vs. 3000 EUR per patient year. An example is given of how to calculate direct cost differences, showing local differences. Randomized comparisons between CSII and MDI in childhood and adolescence show few marked clinical effects, but non-randomized comparisons favor CSII. Quality of life parameters fall short in any such comparison in children and adolescents alike. The reasons for the apparent discrepancy between non-randomized childhood studies and the randomized prospective ones are given. There is a dire need for better parameters to assess the well-being of diabetic children treated by CSII or MDI. Only then is it warranted to estimate the cost-effectiveness of CSII vs. MDI in childhood and adolescence.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Sistemas de Infusión de Insulina/economía , Insulina/administración & dosificación , Adolescente , Adulto , Niño , Análisis Costo-Beneficio , Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus Tipo 1/economía , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Bombas de Infusión Implantables/economía , Países Bajos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL polymorphisms have been described that are associated with MBL serum concentration, impaired function, and diabetic complications. We investigated 86 new-onset juvenile type 1 diabetic patients and compared these with their nondiabetic siblings and healthy unrelated control subjects. Polymorphisms of MBL exon 1 and promoter were determined, and serum concentration and MBL-complex activity were measured. Although the genetic polymorphisms of MBL were not different between patients and control subjects, MBL serum concentration as well as MBL complex activity was significantly higher in new-onset diabetic patients compared with their siblings matched for high-producing MBL genotypes (P = 0.0018 and P = 0.0005, respectively). The increase in MBL complex activity in high-MBL-producing patients could only partially be explained by high MBL production, as demonstrated by an increased MBL complex activity-to-MBL concentration ratio (P = 0.004). We conclude that MBL serum concentration and complex activity are increased in early-onset diabetic patients upon manifestation independently of genetic predisposition to high MBL production, indicating a possible role in the immunopathogenesis of type 1 diabetes, in addition to the adaptive islet autoimmunity.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Lectina de Unión a Manosa/sangre , Adolescente , Autoanticuerpos/sangre , Proteína C-Reactiva/análisis , Niño , Preescolar , Diabetes Mellitus Tipo 1/genética , Femenino , Fructosamina/sangre , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA/análisis , Humanos , Masculino , Lectina de Unión a Manosa/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genéticaRESUMEN
BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.
Asunto(s)
Diabetes Mellitus/genética , Mutación , Canales de Potasio de Rectificación Interna/genética , Análisis Mutacional de ADN , Discapacidades del Desarrollo/genética , Epilepsia/genética , Cara/anomalías , Femenino , Heterocigoto , Humanos , Recién Nacido , Islotes Pancreáticos/metabolismo , Masculino , Linaje , Canales de Potasio de Rectificación Interna/química , Canales de Potasio de Rectificación Interna/metabolismo , Análisis de Secuencia de ADNRESUMEN
Killer cell immunoglobulin-like receptors (KIRs) modulate natural killer cell and T-cell function by interacting with HLA class 1 ligands on target cells. Both KIR and HLA are highly polymorphic. We studied the influence of KIR and HLA class 1 genes on the susceptibility to develop type 1 diabetes. The results showed increased numbers of activating KIR genes in patients compared with control subjects (P = 0.049). The combination of the activating KIR2DS2 gene, together with its putative HLA ligand, was present more frequently in patients than in diabetes high-risk HLA-matched control subjects (P = 0.030). Moreover, our results imply that an increase in activating KIR2DS2-HLA ligand pairs combined with a lack of inhibitory KIR-HLA ligand pairs is associated with an additional risk to develop type 1 diabetes in individuals with diabetes high-risk HLA alleles (P = 0.035). We propose that the genetic imbalance between KIR and their HLA class 1 ligands may enhance the activation of T-cells with a low affinity for pancreatic self-antigens, thereby contributing to the pathogenesis of type 1 diabetes.