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Context: Insulin resistance, glucose alterations, arterial hypertension (HTN), and the renin-angiotensin-aldosterone system (RAAS) are related in adult obesity. This crosstalk is still unexplored in childhood. Objective: Characterize the relationships of fasting and postload glucose and insulin levels with new American Academy of Pediatrics classification of HTN and RAAS in pediatric obesity. Methods: This was a retrospective observational study; 799 pediatric outpatients (11.4 ± 3.1 years) at a tertiary center who were overweight or obese and not yet on diet were included. The main outcome measures were mean and correlations among parameters of a complete clinical and metabolic screening (body mass index, blood pressure, and glucose and insulin levels during an oral glucose tolerance test, and renin and aldosterone levels and their ratio). Results: 774 subjects had all the parameters, of whom 87.6% had HTN (5% elevated blood pressure, 29.2% stage I HTN, and 53.4% stage II HTN). Eighty subjects had 1 or more glucose alterations, and more frequently presented HTN. Blood pressure levels were higher in subjects with glucose alterations than in those with normal glucose levels. Fasting and stimulated glucose and insulin levels were directly related to the HTN stages, and insulin sensitivity was lower in HTN than in normal blood pressure. Aldosterone, renin, and aldosterone-renin ratio (ARR) were similar in sexes, whereas aldosterone was higher in prepubertal individuals. Subjects with impaired glucose tolerance (IGT) had higher renin and lower ARR. Renin was positively correlated with postload glucose, and ARR was negatively correlated with the Homeostatic Model Assessment for Insulin Resistance index. Conclusion: A close relationship exists among insulin resistance, glucose alterations, HTN, and renin in childhood obesity. Specific categories of risk could provide indicators for strict clinical surveillance.
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BACKGROUND: Deep vein thrombosis (DVT) genetic predisposition is partially known. OBJECTIVES: This study aimed at assessing the functional impact of nine ADAMTS13 single nucleotide variants (SNVs) previously reported to be associated as a group with DVT in a burden test and the individual association of selected variants with DVT risk in two replication studies. METHODS: Wild-type and mutant recombinant ADAMTS13 were transiently expressed in HEK293 cells. Antigen and activity of recombinant ADAMTS13 were measured by ELISA and FRETS-VWF73 assays, respectively. The replication studies were performed in an Italian case-control study (Milan study; 298/298 patients/controls) using a next-generation sequencing approach and in a Dutch case-control study (MEGA study; 4306/4887 patients/controls) by TaqMan assays. RESULTS: In vitro results showed reduced ADAMTS13 activity for three SNVs (p.Val154Ile [15%; 95% confidence interval [CI] 14-16], p.Asp187His [19%; 95%[CI] 17-21], p.Arg421Cys [24%; 95%[CI] 22-26]) similar to reduced plasma ADAMTS13 levels of patients carriers for these SNVs. Therefore these three SNVs were interrogated for risk association. The first replication study identified 3 heterozygous carriers (2 cases, 1 control) of p.Arg421Cys (odds ratio [OR] 2, 95%[CI] 0.18-22.25). The second replication study identified 2 heterozygous carriers (1 case, 1 control) of p.Asp187His ([OR] 1.14, 95%[CI] 0.07-18.15) and 10 heterozygous carriers (4 cases, 6 controls) of p.Arg421Cys ([OR] 0.76, 95%[CI] 0.21-2.68). CONCLUSIONS: Three SNVs (p.Val154Ile, p.Asp187His and p.Arg421Cys) showed reduced ex vivo and in vitro ADAMTS13 levels. However, the low frequency of these variants makes it difficult to confirm their association with DVT.
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Proteína ADAMTS13/genética , Polimorfismo de Nucleótido Simple , Trombosis de la Vena/genética , Proteína ADAMTS13/análisis , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Células HEK293 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , MasculinoRESUMEN
BACKGROUND: Neither optimal treatment nor significance of ADAMTS13 (A Desintegrin And Metalloprotease with ThromboSpondin type 1 repeats) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have not been defined yet. The aim of the report is to analyze response to different volumes of plasma exchange (PE), and relationship to ADAMTS13. DESIGN AND METHODS: 28 patients clinically diagnosed with idiopathic TTP (n = 18), secondary TTP (n = 4), atypical HUS (n = 3) and typical HUS (n = 3) manifested 31 acute episodes. Patients were treated with PE in 26, and with plasma transfusion in 5 episodes with additional different therapies. RESULTS: PE volumes were as follows: 1 in 7, 1.5 in 3, 2 in 14, and intensifying schedule (1 to 1.5) in 2 episodes. Procedure number was lower in patients treated with 2 and 1.5 (p = 0.019) than in those treated with 1 volume exchange and PE intensifying, respectively (p = 0.010). PE response rate was 25/26 (96.15%). Exacerbation frequency was higher in idiopathic TTP patients (3/19) treated with 1 compared with patients treated with > 1 volume exchange (p = 0.003). Survival rate was 25/28 (89.29%). ADAMTS13 activity was reduced in 22 with severe deficiency in 14 patients. CONCLUSION: Patients responded to different treatments regardless of ADAMTS13 activity, requiring less PEs with larger volume exchanges.