OBJECTIVE—The Pediatric Quality of Life Inventory (PedsQL) is a modular instrument designed to measure health-related quality of life (HRQOL) in children and adolescents aged 2–18 years. The PedsQL 4.0 Generic Core Scales are child self-report and parent proxy-report scales developed as the generic core measure to be integrated with the PedsQL disease-specific modules. The PedsQL 3.0 Type 1 Diabetes Module was designed to measure diabetes-specific HRQOL. RESEARCH DESIGN AND METHODS—The PedsQL Generic Core Scales and Diabetes Module were administered to 300 pediatric patients with type 1 or type 2 diabetes and 308 parents. RESULTS—Internal consistency reliability for the PedsQL Generic Core Total Scale score (α = 0.88 child, 0.89 parent-report) and most Diabetes Module scales (average α = 0.71 child, 0.77 parent-report) was acceptable for group comparisons. The PedsQL 4.0 distinguished between healthy children and children with diabetes. The Diabetes Module demonstrated intercorrelations with dimensions of generic and diabetes-specific HRQOL. CONCLUSIONS—The results demonstrate the reliability and validity of the PedsQL in diabetes. The PedsQL may be used as an outcome measure for diabetes clinical trials and research.
Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.
OBJECTIVE -Metformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes. RESEARCH DESIGN AND METHODS-This study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10 -16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels Ն7.0 and Յ13.3 mmol/l (Ն126 and Յ240 mg/dl), HbA 1c Ն7.0%, stimulated C-peptide Ն0.5 nmol/l (Ն1.5 ng/ml), and a BMI Ͼ50th percentile for age.RESULTS -Metformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was Ϫ2.4 mmol/l (Ϫ42.9 mg/dl) for metformin compared with ϩ1.2 mmol/l (ϩ21.4 mg/dl) for placebo (P Ͻ 0.001). Mean HbA 1c values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P Ͻ 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin.CONCLUSION -Metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients. Diabetes Care 25:89 -94, 2002T he incidence of type 2 diabetes in children has increased dramatically over the past 10 years. This increase has been linked to increasing prevalence of obesity and progressively sedentary lifestyle in American children (1-6). Insulin, the only FDA approved medication for the treatment of diabetes in children, is the current standard of care, despite its parenteral route of delivery and association with the side effects of weight gain and hypoglycemia. Children with type 2 diabetes need alternative therapies that improve glycemic control, facilitate administration and compliance, do not promote weight gain, and address comorbid conditions.Metformin hydrochloride is an oral antihyperglycemic agent that has been used in many countries for Ͼ40 years, and it has been marketed in the U.S. for the treatment of adult type 2 diabetes since 1995. Metformin improves glycemic control by reducing hepatic glucose production, increasing insulin sensitivity, and reducing intestinal glucose absorption, without increasing insulin secretion (7-9). In adults, metformin is effective as an initial monotherapy to improve glycemia, with a low risk of hypoglycemia, and with potential independent benefits of a lack of weight gain and improved lipid profile (10 -13). The phenotypic constellation of type 2 diabetes (hyperglycemia, obesity, dyslipidemia, and insulin resistance) is similar in adults and children (14). Therefore, it has been reasonable to presume that the pharmacodynamic response t...
SummaryBackgroundKCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.MethodsIn this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.Findings90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol [41·0–56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2–10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5–24·0] vs 4·1 years [1·3–10·2]; p=0·0005). Initial improvement was noted following transfer to sulfo...
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