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Transportadoras de Casetes de Unión a ATP/genética , Diabetes Mellitus/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Canales de Potasio de Rectificación Interna/genética , Receptores de Droga/genética , Compuestos de Sulfonilurea/uso terapéutico , Diabetes Mellitus/genética , Epilepsia/genética , Humanos , Hipoglucemiantes , Recién Nacido , Masculino , Mutación , Receptores de SulfonilureasRESUMEN
OBJECTIVES: The effects of non-occupational physical activity were assessed on the number of years lived with and without disability between age 50 and 80 years. METHODS: Using the GLOBE study and the Longitudinal Study of Aging, multi-state life tables were constructed yielding the number of years with and without disability between age 50 and 80 years. To obtain life tables by level of physical activity (low, moderate, high), hazard ratios were derived for different physical activity levels per transition (non-disabled to disabled, non-disabled to death, disabled to non-disabled, disabled to death) adjusted for age, sex and confounders. RESULTS: Moderate, compared to low non-occupational physical activity reduced incidence of disability (HR 0.66, 95% CI 0.51 to 0.86), increased recovery (HR 1.95, 95% CI 1.32 to 2.87), and represents a gain of disability-free years and a loss of years with disability (male 3.1 and 1.2; female 4.0 and 2.8 years). Performing high levels of non-occupational physical activity further reduced incidence, and showed a higher gain in disability-free years (male 4.1; female 4.7), but a similar reduction in years with disability. CONCLUSION: Among 50-80-year-olds promoting physical activity is a fundamental factor to achieve healthy ageing.
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Personas con Discapacidad/estadística & datos numéricos , Esperanza de Vida , Actividad Motora , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Enfermedad Crónica , Evaluación de la Discapacidad , Escolaridad , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiologíaRESUMEN
BACKGROUND: KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously. METHODS: The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets. RESULTS: This resulted not only in improved glycaemic control (HbA(1c) fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change. CONCLUSIONS: This is the first clear report of cognitive function improving in a patient with the neurological features associated with a K(ATP) channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.
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Cognición/efectos de los fármacos , Discapacidades del Desarrollo/genética , Diabetes Mellitus/genética , Mutación/genética , Canales de Potasio de Rectificación Interna/genética , Compuestos de Sulfonilurea/uso terapéutico , Encéfalo/efectos de los fármacos , Discapacidades del Desarrollo/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/psicología , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , MasculinoRESUMEN
AIM: The transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) is expressed in rodent pancreatic progenitor cells, where it is an important member of the genetic hierarchy that regulates the generation of pancreatic endocrine and exocrine cells. The recent description of an HNF-1beta mutation in a patient with neonatal diabetes suggests that HNF-1beta may also play a key role in human pancreatic B-cell development. We aimed to investigate the role of HNF-1beta mutations in neonatal diabetes and also the impact of HNF-1beta mutations on fetal growth. METHODS: We sequenced the HNF-1beta gene in 27 patients with neonatal diabetes in whom other known genetic aetiologies had been excluded. Birth weight was investigated in 21 patients with HNF-1beta mutations. RESULTS: A heterozygous HNF-1beta mutation, S148L, was identified in one patient with neonatal diabetes diagnosed at 17 days, which rapidly resolved only to relapse at 8 years. This patient had pancreatic atrophy, mild exocrine insufficiency and low birth weight (1.83 kg at 40 weeks' gestation). Intrauterine growth was markedly reduced in patients born to unaffected mothers with a median birth weight of 2.4 kg (range 1.8-3.3) (P = 0.006), median centile weight 3 (0.008-38), and 69% were small for gestational age. CONCLUSION: HNF-1beta mutations are a rare cause of neonatal diabetes as well as pancreatic exocrine and endocrine dysfunction. Low birth weight is a common feature of patients with HNF-1beta mutations and is consistent with reduced insulin secretion in utero. These findings support a key role for HNF-1beta in early pancreatic progenitor cells in man.
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Diabetes Mellitus/genética , Diabetes Gestacional/genética , Retardo del Crecimiento Fetal/genética , Factor Nuclear 1-beta del Hepatocito/genética , Mutación/genética , Enfermedades Pancreáticas/genética , Peso al Nacer , Niño , Diabetes Mellitus/embriología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Páncreas/embriología , Enfermedades Pancreáticas/embriología , Linaje , Embarazo , Efectos Tardíos de la Exposición Prenatal/genéticaRESUMEN
AIMS/HYPOTHESIS: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the K(ATP) channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated K(ATP) channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the K(ATP) channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment. METHODS: We report the response to sulfonylurea treatment in a boy with neonatal diabetes and marked developmental delay resulting from the KCNJ11 mutation V59M. RESULTS: Glibenclamide (glyburide) treatment was started at 23 months and resulted in insulin being discontinued, lower overall glycaemia, reduced glucose fluctuations and reduced hypoglycaemia. Good control (HbA(1c) 6.5%) was maintained 2 years after discontinuing insulin, despite a reduction in the glibenclamide dose (from 0.41 to 0.11 mg.kg(-1).day(-1)). Within 1 month of starting glibenclamide there was marked improvement in motor function, resulting in the patient progressing from being unable to stand unaided to walking independently, but there was no improvement in mental function. CONCLUSIONS/INTERPRETATION: This 2-year follow-up of a patient highlights that sulfonylurea treatment can result in prolonged, excellent glycaemic control and may improve motor features, but not mental features, associated with KCNJ11 mutations. This suggests that the neurological actions of sulfonylurea are initially principally on peripheral (nerve or muscle) rather than on central (brain) K(ATP) channels. Early molecular diagnosis is important in patients with neonatal diabetes and neurological features.
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Glucemia/metabolismo , Discapacidades del Desarrollo/genética , Diabetes Mellitus/genética , Epilepsia/genética , Gliburida/uso terapéutico , Actividad Motora , Mutación , Canales de Potasio de Rectificación Interna/genética , Sustitución de Aminoácidos , Discapacidades del Desarrollo/tratamiento farmacológico , Discapacidades del Desarrollo/fisiopatología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/fisiopatología , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Estudios de Seguimiento , Homeostasis , Humanos , Hipoglucemiantes/uso terapéutico , Recién Nacido , MasculinoRESUMEN
Neonatal diabetes mellitus (DM) is by definition diagnosed within the first 3 months of life and can be either transient (TNDM) or permanent (PNDM). Recently, activating mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the K(ATP) channel, have been identified as a cause of TNDM, the main cause of PNDM, and the cause of a new syndrome: developmental delay, epilepsy and neonatal diabetes. Patients with neonatal DM are normally dependent on life-long insulin injections, but patients with neonatal DM due to a KCNJ11 mutation are able to achieve control with sulphonylurea tablets. The mutations are predominantly spontaneous but have also been described as due to autosomal dominant inheritance and paternal mosaicism. Mutations at codon 201 and 59 are thus far the most prevalent. Because mutated K(ATP) channels do not close in response to ATP, the beta-cell membrane is hyperpolarised and insulin secretion does not occur. Mutated K(ATP) channels in muscle, nerve and brain are responsible for the neurological symptoms.
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Diabetes Mellitus Tipo 1/genética , Mutación , Canales de Potasio de Rectificación Interna/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , Lactante , Recién Nacido , Insulina/metabolismo , Secreción de InsulinaRESUMEN
Two patients came to their general practitioner for relatively minor problems: a 4-year-old boy came with a red eye and a 10-year-old girl with red foot soles. They came from Pakistan and Vietnam respectively. Their symptoms were due to tuberculosis, which diagnosis was established by Mantoux test and culture of a stomach aspirate. They were treated accordingly with isoniazid, rifampicin and pyrazinamide and with isoniazid, rifampicin and ethambutol respectively. These cases stress the importance of knowledge of the extrapulmonary manifestations of tuberculosis. As treatment exists and adequate treatment can diminish the reservoir of tuberculosis bacteria, early diagnosis can prevent the morbidity, spread and mortality of tuberculosis.