142 research outputs found
RhIGF-1 treatment increases bone mineral density and trabecular bone structure in children with PAPP-A2 deficiency
KARGER: "This is the peer-reviewed but unedited manuscript version of the following article: Hormone Research in Paediatrics 89.3 (2018): 200-204 DOI: 10.1159/000486336. The final, published version is available at http://www.karger.com/. http://doi.org/10.1159/000486336]."Aim: Our objective was to determine changes in bone mineral density (BMD), trabecular bone score (TBS), and body composition after 2 years of therapy with recombinant human insulin-like growth factor-1 (rhIGF-1) in 2 prepubertal children with a complete lack of circulating PAPP-A2 due to a homozygous mutation in PAPP-A2 (p.D643fs25∗) resulting in a premature stop codon. Methods: Body composition, BMD, and bone structure were determined by dual-energy X-ray absorptiometry at baseline and after 1 and 2 years of rhIGF-1 treatment. Results: Height increased from 132 to 145.5 cm (patient 1) and from 111.5 to 124.5 cm (patient 2). Bone mineral content increased from 933.40 to 1,057.97 and 1,152.77 g in patient 1, and from 696.12 to 773.26 and 911.51 g in patient 2, after 1 and 2 years, respectively. Whole-body BMD also increased after 2 years of rhIGF-1 from baseline 0.788 to 0.869 g/cm2in patient 1 and from 0.763 to 0.829 g/cm2in patient 2. After 2 years of treatment, both children had an improvement in TBS. During therapy, a slight increase in body fat mass was seen, with a concomitant increase in lean mass. No adverse effects were reported. Conclusion: Two years of rhIGF-1 improved growth, with a tendency to improve bone mass and bone microstructure and to modulate body composition.The authors are funded by Fondos de Investigación Sanitaria and FEDER (Grants PI1302195 and PI1600485 to J.A.), Ministerio de Ciencia e Innovación (BFU2014-51836-C2-2-R to J.A.C.), Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (J.A.), and Fundación Endocrinología y Nutrició
Heterozygous rare genetic variants in non-syndromic early-onset obesity
BACKGROUND: Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. OBJECTIVE: We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). METHODS: Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. RESULTS:Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. CONCLUSIONS: Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.Clara Serra-Juhé, Gabriel Á. Martos-Moreno, Francesc Bou de Pieri, Raquel Flores, Julie A. Chowen, Luis A. Pérez-Jurado, Jesús Argent
Las alteraciones metabólicas asociadas a la obesidad están ya presentes en los primeros años de vida: estudio colaborativo español
Los objetivos de este estudio son, realizar una descrip-ción de las características demográficas, antropométricas y de las alteraciones metabólicas de niños atendidos por obe-sidad resaltando las características aquellos casos de obesidad de inicio temprano (< 10 años) y los de inicio precoz (< 5 años), y evaluar la capacidad diagnóstica de la definición de síndrome metabólico (SM) según diferentes criterios.
Métodos: Es un estudio retrospectivo, caso-control, trans-versal, multicéntrico. Han participado un total de 10 Uni-dades de Endocrinología Pediátrica de diferentes hospitales españoles con un grupo de 469 niños con obesidad de inicio temprano y otro grupo de 30 niños con obesidad de inicio precoz. El grupo control estuvo constituido por 224 niños sanos menores de 10 años. Se realizó una valoración antro-pométrica y determinación analítica de parámetros del me-tabolismo de los hidratos de carbono y lipidograma.
Resultados: La presencia de alteraciones metabólicas asociadas a la obesidad en la etapa infanto-juvenil en Espa-ña es notable, de forma aislada, o englobada bajo la defini-ción de SM. La prevalencia de éste aumenta sustancialmen-te cuando se considera la resistencia periférica a la acción de la insulina como criterio diagnóstico. Se demuestra cómo en niños menores de 10 años, dichas alteraciones están presen-tes en un porcentaje reseñable, y se encuentran las primeras alteraciones metabólicas ya en niños obesos < 5 años.
Conclusión: En los niños españoles existen alteracio-nes metabólicas asociadas a la obesidad en la etapa in-fanto-juvenil de forma aislada o englobada bajo la de-finición de SM, y ya están presentes a edades precoces.
The objectives of this study are to provide a description of the demographic, anthropometric characteristics and metabolic abnormalities in children with early-onset (< 10 years) and of very-early-onset obesity (< 5 years). We also evaluate the diagnostic ability using the definition of meta-bolic syndrome (MS) according to different criteria.
Methods: It is a retrospective, case-control, cross-sec-tional, multicenter study. A total of 10 Pediatric Endo-crinology Units in different Spanish hospitals were in-volved. A group of 469 children with early-onset obesity and another group of 30 children with very early-onset obesity were studied. The control group consisted of 224 healthy children younger than 10 years. Anthropometric and analytical determination of carbohydrates metabo-lism parameters and the lipid profile were performed.
Results: The presence of metabolic alterations associa-ted with obesity in children and adolescents in Spain is remarkable, either on their own, or encompassed within the definition of MS. This prevalence increases substan-tially when considering the peripheral resistance to in-sulin action as a diagnostic criterion. It also shows how children who could not be diagnosed with MS according to the definition provided by the International Diabetes Federation (IDF) due to age below 10 years, these altera-tions are already present in a remarkable percentage. In fact, metabolic abnormalities are already present in the very-early-onset obese children (<5 years).
Conclusion: In Spanish children there are metabolic alterations associated with obesity in the infant-juvenile stages alone or encompassed within the definition of MS, and are already present at earlier ages
Nonlinear Effects in Models of the Galaxy: 1. Midplane Stellar Orbits in the Presence of 3D Spiral Arms
With the aim of studying the nonlinear stellar and gaseous response to the
gravitational potential of a galaxy such as the Milky Way, we have modeled 3D
galactic spiral arms as a superposition of inhomogeneous oblate spheroids and
added their contribution to an axisymmetric model of the Galactic mass
distribution. Three spiral loci are proposed here, based in different sets of
observations. A comparison of our model with a tight-winding approximation
shows that the self-gravitation of the whole spiral pattern is important in the
middle and outer galactic regions. As a first step to full 3D calculations the
model is suitable for, we have explored the stellar orbital structure in the
midplane of the Galaxy. We present the standard analysis in the pattern
rotating frame, and complement this analysis with orbital information from the
Galactic inertial frame. Prograde and retrograde orbits are defined
unambiguously in the inertial frame, then labeled as such in the Poincar\'e
diagrams of the non-inertial frame. In this manner we found a sharp separatrix
between the two classes of orbits. Chaos is restricted to the prograde orbits,
and its onset occurs for the higher spiral perturbation considered plausible in
our Galaxy.Comment: 23 pages, 22 Figures. Latex. Submitted to Ap
VAMOS: a Pathfinder for the HAWC Gamma-Ray Observatory
VAMOS was a prototype detector built in 2011 at an altitude of 4100m a.s.l.
in the state of Puebla, Mexico. The aim of VAMOS was to finalize the design,
construction techniques and data acquisition system of the HAWC observatory.
HAWC is an air-shower array currently under construction at the same site of
VAMOS with the purpose to study the TeV sky. The VAMOS setup included six water
Cherenkov detectors and two different data acquisition systems. It was in
operation between October 2011 and May 2012 with an average live time of 30%.
Besides the scientific verification purposes, the eight months of data were
used to obtain the results presented in this paper: the detector response to
the Forbush decrease of March 2012, and the analysis of possible emission, at
energies above 30 GeV, for long gamma-ray bursts GRB111016B and GRB120328B.Comment: Accepted for pubblication in Astroparticle Physics Journal (20 pages,
10 figures). Corresponding authors: A.Marinelli and D.Zaboro
What to consider when pseudohypoparathyroidism is ruled out: IPPSD and differential diagnosis
Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright''s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes
Efficacy and safety of preoperative preparation with Lugol''s iodine solution in euthyroid patients with Graves’ disease (LIGRADIS Trial): Study protocol for a multicenter randomized trial
Background: Currently, both the American Thyroid Association and the European Thyroid Association recommend preoperative preparation with Lugol''s Solution (LS) for patients undergoing thyroidectomy for Graves’ Disease (GD), but their recommendations are based on low-quality evidence. The LIGRADIS trial aims to provide evidence either to support or refute the systematic use of LS in euthyroid patients undergoing thyroidectomy for GD. Methods: A multicenter randomized controlled trial will be performed. Patients =18 years of age, diagnosed with GD, treated with antithyroid drugs, euthyroid and proposed for total thyroidectomy will be eligible for inclusion. Exclusion criteria will be prior thyroid or parathyroid surgery, hyperparathyroidism that requires associated parathyroidectomy, thyroid cancer that requires adding a lymph node dissection, iodine allergy, consumption of lithium or amiodarone, medically unfit patients (ASA-IV), breastfeeding women, preoperative vocal cord palsy and planned endoscopic, video-assisted or remote access surgery. Between January 2020 and January 2022, 270 patients will be randomized for either receiving or not preoperative preparation with LS. Researchers will be blinded to treatment assignment. The primary outcome will be the rate of postoperative complications: hypoparathyroidism, recurrent laryngeal nerve injury, hematoma, surgical site infection or death. Secondary outcomes will be intraoperative events (Thyroidectomy Difficulty Scale score, blood loss, recurrent laryngeal nerve neuromonitoring signal loss), operative time, postoperative length of stay, hospital readmissions, permanent complications and adverse events associated to LS. Conclusions: There is no conclusive evidence supporting the benefits of preoperative treatment with LS in this setting. This trial aims to provide new insights into future Clinical Practice Guidelines recommendations. Trial registration: ClinicalTrials.gov identifier: NCT03980132. © 202
Inflammatory Adipokines, High Molecular Weight Adiponectin, and Insulin Resistance: A Population-Based Survey in Prepubertal Schoolchildren
BackgroundThe aim of this study was to investigate sex differences and associations of high molecular weight (HMW) adiponectin, leptin and proinflammatory adipokines, individually or in combinations, with adiposity and insulin resistance (IR) measures in prepubertal childhood.MethodologyWe studied 305 prepubertal children (boys/girls: 144/161; Tanner stage 1; age: 5-13 yr), included in a cohort of 44,231 adolescents who participated in an extensive Italian school-based survey. According to Cole's criteria, 105 individuals were lean (L; boys/girls: 59/46), 60 overweight (OW; boys/girls: 32/28) and 140 obese (OB; boys/girls: 70/70). Measurements comprised total and HMW adiponectin, leptin, as well as a panel of proinflammatory adipokines/chemokines associated with diabetes risk.Principal findingsLeptin-, and the leptin-to-HMW adiponectin ratio (L/HMW)-, increased progressively (pConclusionsIn prepubertal children, leptin emerges as a sex-independent discrimination marker of adiposity degree and as a useful, sex-associated predictor of the systemic insulin resistance
Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement
This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders
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