Evaluating a childhood obesity program with the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework.

Primary care providers can use behavioral lifestyle interventions to effectively treat children with overweight and obesity, but implementing these interventions is challenging. Most childhood obesity intervention evaluation studies focus on effectiveness. Few studies describe implementation. Our goal was to evaluate critical components of a childhood obesity intervention in primary care. We conducted a pilot implementation study of an existing structured lifestyle intervention in the Canton of Bern, Switzerland from 2013 to 2015. The intervention consisted of 10 sessions, led by a primary care physician. It included children aged 6-8 years old, with BMI over the 90th age-adjusted percentile. We used the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) evaluation framework to describe the pilot implementation study. We stratified description of RE-AIM components at the patient- and physician-level. For Reach: 864 children were screened; 65 were overweight; 394 physicians were invited to participate in the study. For Effectiveness: BMI z-score significantly decreased (-5.6%, p = 0.01). For Adoption: 14 participating physicians treated 26 patients. Implementation: the mean number of consultations was 8. For Maintenance: 9 (35%) children discontinued the intervention; 7 (50%) of physicians continued to apply at least one component of the intervention. The summarized components of the program within the RE-AIM framework suggest the program was successful. Stakeholders can use our results if they intend to disseminate and evaluate similar interventions in different settings

A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form

Background: More than 90% of Congenital Adrenal Hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the HLA class III area on the short arm of chromosome 6p21.3. In this region, a 30 kb deletion produces a non functional chimeric gene with its 5′ and 3′ ends corresponding to CYP21A1P pseudogene and CYP21A2, respectively. To date, five different CYP21A1P/CYP21A2 chimeric genes have been found and characterized in recent studies. In this paper, we describe a new CYP21A1P/CYP21A2 chimera (CH-6) found in an Italian CAH patient. Methods Southern blot analysis and CYP21A2 sequencing were performed on the patient. In addition, in order to isolate the new CH-6 chimeric gene, two different strategies were used. Results: The CYP21A2 sequencing analysis showed that the patient was homozygote for the g.655C/A<G mutation and heterozygote for the p.P30L missense mutation. In addition, the promoter sequence revealed the presence, in heterozygosis, of 13 SNPs generally produced by microconversion events between gene and pseudogene. Southern blot analysis showed that the woman was heterozygote for the classic 30-kb deletion producing a new CYP21A1P/CYP21A2 chimeric gene (CH-6). The hybrid junction site was located between the end of intron 2 pseudogene, after the g.656C/A<G mutation, and the beginning of exon 3, before the 8 bp deletion. Consequently, CH-6 carries three mutations: the weak pseudogene promoter region, the p.P30L and the g.655C/A<G splice mutation. Conclusion: We describe a new CYP21A1P/CYP21A2 chimera (CH-6), associated with the HLA-B15, DR13 haplotype, in a young Italian CAH patient. © 2009 Concolino et al; licensee BioMed Central Ltd

Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease

ObjectivesGraves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy.MethodsRetrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis.ResultsData from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity.DiscussionWe present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases

Report drawn up on behalf of the Committee on Economic and Monetary Affairs on the proposal from the Commission of the European Communities to the Council (Doc. 1-99/83-COM(83) 85 final) for a Council Decision implementing the decision empowering the Commission to borrow under the New Community Instrument for the purpose of promoting investment within the Community, Working Documents 1983-1984, Document 1-236/83, 3 May 1983

The 4MOST([1]) instrument is a concept for a wide-field, fibre-fed high multiplex spectroscopic instrument facility on the ESO VISTA telescope designed to perform a massive (initially >25x10(6) spectra in 5 years) combined all-sky public survey. The main science drivers are: Gaia follow up of chemo-dynamical structure of the Milky Way, stellar radial velocities, parameters and abundances, chemical tagging; eROSITA follow up of cosmology with x-ray clusters of galaxies, X-ray AGN/galaxy evolution to z similar to 5, Galactic X-ray sources and resolving the Galactic edge; Euclid/LSST/SKA and other survey follow up of Dark Energy, Galaxy evolution and transients. The surveys will be undertaken simultaneously requiring: highly advanced targeting and scheduling software, also comprehensive data reduction and analysis tools to produce high-level data products. The instrument will allow simultaneous observations of similar to 1600 targets at R similar to 5,000 from 390-900nm and similar to 800 targets at R>18,000 in three channels between similar to 395-675nm (channel bandwidth: 45nm blue, 57nm green and 69nm red) over a hexagonal field of view of similar to 4.1 degrees2. The initial 5-year 4MOST survey is currently expect to start in 2020. We provide and overview of the 4MOST systems: opto-mechanical, control, data management and operations concepts; and initial performance estimates

Novel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency

<p>Abstract</p> <p>Background</p> <p>Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by deletions, large gene conversions or mutations in <it>CYP21A2 </it>gene. The human gene is located at 6p21.3 within a <it>locus </it>containing the genes for putative serine/threonine Kinase <it>RP</it>, complement <it>C4</it>, steroid 21-hydroxylase <it>CYP21 </it>tenascin <it>TNX</it>, normally, in a duplicated cluster known as RCCX module. The <it>CYP21 </it>extra copy is a pseudogene (<it>CYP21A1P</it>). In Brazil, 30-kb deletion forming monomodular alleles that carry chimeric <it>CYP21A1P/A2 </it>genes corresponds to ~9% of disease-causing alleles. Such alleles are considered to result from unequal crossovers within the bimodular <it>C4/CYP21 locus</it>. Depending on the localization of recombination breakpoint, different alleles can be generated conferring the locus high degree of allelic variability. The purpose of the study was to investigate the variability of deleted alleles in patients with 21-hydroxylase deficiency.</p> <p>Methods</p> <p>We used different techniques to investigate the variability of 30-kb deletion alleles in patients with 21-hydroxylase deficiency. Alleles were first selected after Southern blotting. The composition of <it>CYP21A1P/A2 </it>chimeric genes was investigated by ASO-PCR and MLPA analyses followed by sequencing to refine the location of recombination breakpoints. Twenty patients carrying at least one allele with <it>C4/CYP21 </it>30-kb deletion were included in the study.</p> <p>Results</p> <p>An allele carrying a <it>CYP21A1P/A2 </it>chimeric gene was found unusually associated to a <it>C4B/C4A </it><it>Taq </it>I 6.4-kb fragment, generally associated to <it>C4B </it>and <it>CYP21A1P </it>deletions. A novel haplotype bearing both p.P34L and p.H62L, novel and rare mutations, respectively, was identified in exon 1, however p.P30L, the most frequent pseudogene-derived mutation in this exon, was absent. Four unrelated patients showed this haplotype. Absence of p.P34L in <it>CYP21A1P </it>of normal controls indicated that it is not derived from pseudogene. In addition, the combination of different approaches revealed nine haplotypes for deleted 21-hydroxylase deficiency alleles.</p> <p>Conclusions</p> <p>This study demonstrated high allelic variability for 30-kb deletion in patients with 21-hydroxylase deficiency indicating that a founder effect might be improbable for most monomodular alleles carrying <it>CYP21A1P/A2 </it>chimeric genes in Brazil.</p

SnoRNA Snord116 (Pwcr1/MBII-85) Deletion Causes Growth Deficiency and Hyperphagia in Mice

Prader-Willi syndrome (PWS) is the leading genetic cause of obesity. After initial severe hypotonia, PWS children become hyperphagic and morbidly obese, if intake is not restricted. Short stature with abnormal growth hormone secretion, hypogonadism, cognitive impairment, anxiety and behavior problems are other features. PWS is caused by lack of expression of imprinted genes in a ∼4 mb region of chromosome band 15q11.2. Our previous translocation studies predicted a major role for the C/D box small nucleolar RNA cluster SNORD116 (PWCR1/HBII-85) in PWS. To test this hypothesis, we created a ∼150 kb deletion of the >40 copies of Snord116 (Pwcr1/MBII-85) in C57BL/6 mice. Snord116del mice with paternally derived deletion lack expression of this snoRNA. They have early-onset postnatal growth deficiency, but normal fertility and lifespan. While pituitary structure and somatotrophs are normal, liver Igf1 mRNA is decreased. In cognitive and behavior tests, Snord116del mice are deficient in motor learning and have increased anxiety. Around three months of age, they develop hyperphagia, but stay lean on regular and high-fat diet. On reduced caloric intake, Snord116del mice maintain their weight better than wild-type littermates, excluding increased energy requirement as a cause of hyperphagia. Normal compensatory feeding after fasting, and ability to maintain body temperature in the cold indicate normal energy homeostasis regulation. Metabolic chamber studies reveal that Snord116del mice maintain energy homeostasis by altered fuel usage. Prolonged mealtime and increased circulating ghrelin indicate a defect in meal termination mechanism. Snord116del mice, the first snoRNA deletion animal model, reveal a novel role for a non-coding RNA in growth and feeding regulation

Structured relaxation in the treatment of akathisia: case series

Purpose: Akathisia remains a common side effect especially from antipsychotic medication.If the condition is diagnosed the management options are limited.Subjects/methodology: We tested a structured relaxation program on nine patients with adiagnosis of schizophrenia suffering from akathisia. All patients were rated on Barnes AkathisiaScale (BAS) before the relaxation program, immediately after and again one week later.Results: The mean BAS score was before the relaxation 3.3 which reduced to 1.4 immediatelyafter to finally 1.0 a week later. A Wilcoxon signed ranks test revealed a significant reduction inBAS score from baseline to endpoint (P = 0.026; Z = -2.232) and a highly significant reductionfrom baseline to follow-up (P = 0.008; Z = -2.636).Discussion: Although the study has a number of limitations the relaxation program appearsto be a promising alternative to traditional treatment of akathisia. The patients appreciated therelaxation session but none of them managed to carry it out on their own without professionalencouragement. The findings in this case series warrant further investigation with larger numbersof patients.<br/

Untersuchungen zur normalen und pathologischen Steuerung der Nebennierenrinden-Androgene im Kindesalter

Die Reifung der Zona reticularis der Nebennieren-Rinden (NNR) und ihrer Androgen-Sekretion vor der Pubertät unterscheidet sich bei Menschen und höheren Primaten von der NNR-Reifung anderer Species, z.B. der Nager. Die Sekretion der NNR-Androgene leitet die Pubertätsentwicklung ein. Die NNR-Androgene erlangen medizinische Bedeutung dadurch, dass sie bei Frauen zu Hirsutismus und Fertilitätsstörungen führen können. Neben diesen Symptomen stellen sie einen Risikofaktor für die Entwicklung eines Polycystischen-Ovar-Syndroms (PCOS) dar, das ungefähr 7 % der prämenopausalen Frauen betrifft. Lange Zeit war nicht bekannt, wie die Differenzierung der Zona reticularis beim Menschen reguliert wird. Sicher ist ACTH bei weitem das bedeutsamste übergeordnete Hormon für die globale adrenocorticale Differenzierung und Funktion. Weitere Faktoren sind speziell für die Androgensekretion verantwortlich, aber nicht genau definiert. Nun wurde zunächst in zellbiologischen Experimenten belegt, dass die ACTH-Wirkung durch ein Spezies-spezifisches Muster von Wachstumsfaktoren autokrin moduliert wird und so die postnatale Entwicklung der Nebenniere steuern kann. Die vorliegenden Untersuchungen an menschlichen NNR-Zellen von Kindern und Erwachsenen in Primärkultur zeigen erstmals, dass IGF-I und IGF-II differenzierte Funktionen dieser Zellen aufrecht erhalten. IGF-I und, mehr noch, IGF-II steigern die Steroid-Biosynthese und ACTH-Ansprechbarkeit, und sie fördern die Bildung von Androstendion, einem delta5-Androgen der Zona reticularis. Darüberhinaus bewirkt Insulin in physiologischen sowie in micromolaren Konzentrationen den IGFs ähnliche Änderungen der Steroidsynthese. In Querschnittsuntersuchungen an gesunden Kindern vor der Pubertät sowie Kindern mit einfacher Adipositas konnte gezeigt werden, dass die Körperzusammensetzung mit den NNR-Androgenen zusammenhängt. Über die Mediatoren IGF-I, Insulin und Leptin wird offensichtlich der NNR der Zustand von Gewicht und Wachstum des Kindes signalisiert, auch bei pathologischer Körperzusammensetzung, wie dem Prader-Willi-Syndrom. Während die Adipositas die Androgen-Bildung steigern kann, ist sie jedoch selbst nicht der kausale Faktor einer vorzeitigen Nebennierenrindenreifung. Der Prämaturen Pubarche können in 5 - 10 % der untersuchten weiblichen Population ein nicht-klassisches AGS oder NNR-Tumoren zugrunde liegen. Bei den verbleibenden Kindern besteht eine eigentlich harmlose Reifungsbeschleunigung mit normaler Wachstumsprognose. Betrachtet man diese Kinder mit idiopatischer Prämaturer Adrenarche jedoch genauer, so finden sich zwei Untergruppen mit langfristigen Risiken: erstens zeigen Kinder mit einer sogenannte manifesten Heterozygotie für einen 21-Hydroxylase-Defekt Auffälligkeiten des Wachstums, die eine Endgrössenreduktion bewirken könnten, und zweitens wird bei Jugendlichen mit einer Überstimulierbarkeit der NNR diese "Exaggerated Adrenarche" für ein nachfolgendes PCOS verantwortlich gemacht. Schliesslich scheint es vor dem Hintergrund der sich epidemieartig ausbreitenden Zunahme des Übergewichts im Kindesalter angezeigt, den Bezug dieser NNR-Störungen zur Adipositas und der Hyperinsulinämie weiter zu klären.The prepubertal maturation of the zona reticularis of the adrenal cortex and its androgen secretion in man and higher primates differs from other species, e.g. rodents. The secretion of adrenal androgens induces the pubertal development. The importance of adrenal androgens is derived from them being the cause for hirsutism and fertility disorders in women. In addition they represent a risk factor for the development of the polycystic ovary syndrome (PCOS), that affects about 7% of all pre-menopausal women. The regulation of the differentiation of the zona reticularis was unknown for a long time. However, ACTH is by far the most important hormone to regulate the global adrenocortical differentiation and function. In addition, other yet undefined factors are specifically responsible for the secretion of adrenal androgens. The cell-biological experiments presented here demonstrate that the effects of ACTH can be modulated in an autocrine manner by a species-specific pattern of growth factors so as to allow for the control of the postnatal development of the adrenal gland. The present investigations in human adrenocortical cells of children and adults in primary culture show for the first time that IGF-I and IGF-II maintain the differentiated function of these cells. IGF-I and to an even greater extent IGF-II enhance the biosynthesis of steroids and ACTH-responsiveness, and they promote the production of androstenedione, a delta5-androgen of the zona reticularis. Moreover, insulin, in physiological as well as in micromolar concentrations, induces changes in steroid production similar to the IGFs. In cross-sectional studies of healthy pre-pubertal children and children with simple obesity, it was shown that body composition is associated with adrenal androgens. Mediated by IGF-I, insulin and leptin, body composition apparently signals the child's state of weight and growth to the adrenals, even in patients with abnormal body composition, e.g. the Prader-Willi syndrome. While obesity may enhance androgen production, it is not the direct causal factor to induce premature adrenal maturation. In 5-10% of the female population investigated, premature pubarche is caused by non-classical adrenal hyperplasia or an adrenocortical tumour. In the remaining children, there is merely a harmless acceleration of maturation with normal growth prediction. A closer look at the children with idiopathic premature adrenarche, however, reveals two subgroups with long-term risks: First, children with a so called manifest heterozygosity of a 21-hydroxylase-defect show growth abnormalities, possibly reducing final height. Second, in adolescents with enhanced stimulation of the adrenal cortex, this 'exaggerated adrenarche' is held responsible for the subsequent development of PCOS. Finally, with regard to the rapidly spreading epidemic of overweight in children, it seems essential to study into greater depth the relationship between these adrenal dysfunctions and obesity or hyperinsulinism

The increase of fatty acid-binding protein aP2 in overweight and obese children: interactions with dietary fat and impact on measures of subclinical inflammation

BACKGROUND: In adults, circulating aP2 may link obesity, inflammation and the metabolic syndrome, but there are few data in children. Experimental models support that dietary factors, particularly dietary fat, may be major determinants of phenotype. OBJECTIVE: The aim of this study was to investigate, in normal, overweight and obese children, the relationships among aP2, the metabolic syndrome, inflammation and diet. DESIGN: This was a cross-sectional study conducted in Northern Switzerland. SUBJECTS: Subjects for this study were 6- to 14-year-old, prepubertal and early pubertal, normal weight, overweight and obese children (n=124). MAIN OUTCOME MEASURES: Body mass index (BMI), body fat percent, waist-to-hip ratio, blood pressure, circulating aP2, fasting insulin, C-reactive protein (CRP), plasma lipids and dietary intakes of macro- and micronutrients were determined. RESULTS: Circulating aP2 markedly increased with increasing central and total adiposity, and predicted measures of insulin resistance. Independent of BMI standard deviation scores and puberty, aP2 correlated with intake of the antioxidant vitamins A, C and E as well as circulating concentrations of CRP, leptin and low-density lipoprotein cholesterol. Children with lower aP2 concentrations consuming high-fat diets did not show an increase in fasting insulin or CRP, whereas those with higher aP2 concentrations showed marked increases in these measures with high intakes of fat or saturated fat. CONCLUSIONS: Increased central and overall adiposity in children are associated with higher circulating aP2 concentrations. In children with high dietary intakes of total fat and saturated fat, but not those with low intakes, higher aP2 concentrations are associated with measures of insulin resistance and inflammation

Aus dem Leben der Familia Gg. Chrn. Gail u. Christiane Gail, geb. Pfitzer

Arnold Konrad Christian L'Alleman