Pulse pressure in children and adolescents with type 1 diabetes mellitus in Germany and Austria

Background: Impaired blood pressure regulation contributes to the development of diabetic complications. The influence of systolic (SBP) vs. diastolic blood pressure (DBP) is still controversial. Peripheral pulse pressure (PP), the difference between SBP and DBP, is an indicator for arterial stiffness. Only little data are available for PP in children. Therefore, we studied PP regulation in type 1 diabetic children and adolescents. Methods: Blood pressure values of 46737 patients with T1DM younger than 20years are documented in the DPV database and were compared with the control populations of the '4th report on high blood pressure (4th report)' and the German KIGGS study. Results: PP is increased in 63% (4th report) or 67% (KIGGS) of the patients, respectively. The rate of increased PP remains stable between 59 and 68%, irrespective of sex, age, and the control population. Absolute PP is elevated independently of the control population (PP T1DM 49.13±11.1 vs. 4th report 45.38±3 vs. KIGGS 44.58±4.6 mmHg; all p<0.0001, Wilcoxon test) and increases with age in both sexes. Age, male sex, diabetes duration, insulin dose, and body mass index (BMI) are independent factors contributing to elevated absolute PP levels and to the prevalence of wide PP. HbA1c is negligible negatively related to increased PP levels (multiple linear regression). Conclusions: In T1DM increased PP is a marker for accelerated arterial stiffness and aging and should be considered as an additional risk factor in the treatment of diabetic children. Elevated PP in children with T1DM may contribute to the high risk for early development of atherosclerosis

CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells

A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G(1)/G(0) phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation- inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma

Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency.

2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union. 63% of the study participants presented with a metabolic decompensation while most others were identified via newborn screening or family studies. In symptomatic patients, age at manifestation ranged between 5months and 6.8years. Only 7% developed a major mental disability while the vast majority was cognitively normal. More than one third of the identified mutations in ACAT1 are intronic mutations which are expected to disturb splicing. We identified several novel mutations but, in agreement with previous reports, no clear genotype-phenotype correlation could be found. Our study underlines that the prognosis in MAT deficiency is good and MAT deficient individuals may remain asymptomatic, if diagnosed early and preventive measures are applied

Clinical presentation and outcome in a series of 88 patients with the cblC defect.

The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors. RESULTS: No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with "overall impression" as judged by treating physicians. Physician's impression of patient's well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C&gt;T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria

Management of phenylketonuria in Europe: Survey results from 19 countries

To gain better insight in the most current diagnosis and treatment practices for phenylketonuria (PKU) from a broad group of experts, a European PKU survey was performed. The questionnaire. consisting of 33 questions, was sent to 243 PKU professionals in 165 PKU centers in 23 European countries. The responses were compiled and descriptive analyses were performed. One hundred and one questionnaires were returned by 93/165 centers (56%) from 19/23 European countries (83%). The majority of respondents (77%) managed patients of all age groups and more than 90% of PKU teams included physicians or dieticians/nutritionists. The greatest variability existed especially in the definition of PKU phenotypes, therapeutic blood phenylalanine (Phe) target concentrations, and follow-up practices for PKU patients. The tetrahydrobiopterin (BH4: sapropterin) loading test was performed by 54% of respondents, of which 61% applied a single dose test (20 mg/kg over 24 h). BH4 was reported as a treatment option by 34%. This survey documents differences in diagnostic and treatment practices for PKU patients in European centers. In particular, recommendations for the treatment decision varied greatly between different European countries. There is an urgent need to pool long-term data in PKU registries in order to generate an evidence-based international guideline