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

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

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

Comment traiter l'obésité de l'enfant? : Importance de la prévention primaire

The prevalence of childhood obesity increases dramatically. First signs of cardiovascular diseases and type 2 diabetes appear early in life. The treatment of childhood obesity aims at weight maintenance during growth, normalization of body mass index at long-term and prevention of complications. The family based behavioural therapy is a promising approach. It provides simultaneous treatment for the overweight parent and child in order to modify the family environment, to provide role models and support for child behaviour changes. However, this requires group leaders and multiple counselors to meet with families. The treatment should be initiated as soon as possible, as its efficacy is reduced after the onset of puberty. Early preventive interventions that aim to modify both individual's behaviours and the environment are needed

Comment traiter de l'obésité de l'enfant ? Importance de la prévention primaire

The prevalence of childhood obesity increases dramatically. First signs of cardiovascular diseases and type 2 diabetes appear early in life. The treatment of childhood obesity aims at weight maintenance during growth, normalization of body mass index at long-term and prevention of complications. The family based behavioural therapy is a promising approach. It provides simultaneous treatment for the overweight parent and child in order to modify the family environment, to provide role models and support for child behaviour changes. However, this requires group leaders and multiple counselors to meet with families. The treatment should be initiated as soon as possible, as its efficacy is reduced after the onset of puberty. Early preventive interventions that aim to modify both individual's behaviours and the environment are needed

[How to treat childhood obesity? Importance of primary prevention]

The prevalence of childhood obesity increases dramatically. First signs of cardiovascular diseases and type 2 diabetes appear early in life. The treatment of childhood obesity aims at weight maintenance during growth, normalization of body mass index at long-term and prevention of complications. The family based behavioural therapy is a promising approach. It provides simultaneous treatment for the overweight parent and child in order to modify the family environment, to provide role models and support for child behaviour changes. However, this requires group leaders and multiple counselors to meet with families. The treatment should be initiated as soon as possible, as its efficacy is reduced after the onset of puberty. Early preventive interventions that aim to modify both individual's behaviours and the environment are needed

Clinical, genetic and functional characteristics of three novel CYP17A1 mutations causing combined 17alpha-hydroxylase/17,20-lyase deficiency

BACKGROUND: P450c17 has two distinct activities: 17alpha-hydroxylase activity and 17,20-lyase activity. Combined 17alpha-hydroxylase/17,20-lyase deficiency leads to a severe defect in the production of cortisol and sex steroids. In affected males this results in impaired masculinization with ambiguous or female external genitalia. Female patients have normal genitalia but show a lack of pubertal development in adolescence. An increased production of mineralocorticoids often leads to hypertension and hypokalemia in both sexes. METHODS: To better understand the mechanisms of P450c17 deficiency, we studied 2 patients (both 46,XY) with combined 17alpha-hydroxylase/17,20-lyase deficiency of different severity: one with complete lack of masculinization and one with ambiguous genitalia. RESULTS: Four mutations were identified by sequencing of the CYP17A1 gene: I332T and A355T in the less severely affected patient; G111S and R440H in the patient with complete lack of masculinization. The three novel mutations were expressed in COS1 cells and all mutant proteins except I332T showed a complete loss of both enzymatic activities. I332T retained some residual 17alpha-hydroxylase as well as 17,20-lyase activity. CONCLUSION: We identified 2 patients with the phenotypical spectrum of P450c17 deficiency. Three novel mutations in the CYP17A1 gene were identified and their functional characterization provided a good phenotype-genotype correlation. The location of the mutated residues in the three-dimensional model of P450c17 gave some additional insights into its structure-function relationship

Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart-Willi syndrome

CONTEXT: The specific form of hypogonadism in Prader-Labhart-Willi syndrome (PWS), central or peripheral, remains unexplained. OBJECTIVES: The objectives of this study were to investigate the cause of hypogonadism in PWS and determine whether human chorionic gonadotropin (hCG) treatment can restore pubertal development. DESIGN: This was a clinical follow-up study, divided into two samples, over a duration of 1.5 and 4.5 yr. PATIENTS: Eight male infants and six peripubertal boys (age at start of observation, 0.06-0.93 and 8.1-10.8 yr, respectively) with genetically confirmed PWS were studied. INTERVENTION: hCG (500-1500 U twice weekly) was given from age 13.5 yr to the present. MAIN OUTCOME MEASURES: Serum FSH, LH, inhibin B, and testosterone levels and pubertal development were the main outcome measures. RESULTS: Infants with PWS presented normal LH (2.3 +/- 0.7 U/liter) and testosterone (2.5 +/- 0.9 nmol/liter) levels (mean +/- sem at 5 months) compared with the reference range. However, two thirds of the boys displayed cryptorchidism. Inhibin B levels were at the lowest level of the normal range and decreased significantly between infancy and puberty (at 13 yr, 72 +/- 17 pg/ml), whereas FSH secretion increased (9.9 +/- 2.6 U/liter). Pubertal maturation stopped at an average bone age of 13.9 yr. hCG therapy increased testosterone (11 +/- 2 nmol/liter) and reduced FSH (at 16 yr, 1.1 +/- 0.9 U/liter) levels. Testicular volume (5.6 +/- 1 ml) and inhibin B (26.5 +/- 11.9 pg/ml) remained low. CONCLUSION: Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (low inhibin B and high FSH) hypogonadism, suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss. hCG therapy stimulates testosterone production and virilization