Girls and Boys Have a Different Cardiometabolic Response to Obesity Treatment.

Background: Childhood obesity exposes individuals to cardiometabolic disturbances. We analyzed how family-based multidisciplinary obesity treatment influenced children's cardiometabolic health. Materials and methods: In this retrospective, two-year, follow-up study of 654 2- to 18-year-old children treated for obesity in three Finnish pediatric clinics in 2005-2012, blood pressure (BP), metabolic parameters, and the influence of sex, puberty and a change in body mass index standard deviation score (BMI SDS) were analyzed. Results: At baseline, at least one cardiovascular risk factor was present in 474 (80%) cases. Boys presented with more significant changes in cardiometabolic parameters than girls during the treatment. Boys' total cholesterol (TC) improved by 12 months (P = 0.009), and their low-density lipoprotein C (LDL-C) and glycosylated hemoglobin ameliorated by 12 months (P = 0.030 and 0.022, respectively) and 24 months (P = 0.043 and 0.025, respectively). Boys' triglycerides, insulin, homeostasis model assessment for insulin resistance (HOMA-IR) and systolic BP deteriorated at 24 months (P < 0.001, 0.004, 0.002, and 0.037, respectively). In all children, the number of acceptable TC, LDL-C, insulin, and HOMA-IR values increased if BMI SDS reduced 0.25 or more by 12 months. Conclusion: Minor cardiometabolic improvements were found during the obesity treatment. These findings indicate the need to assess treatment methods and focus on prevention.

Paediatric obesity treatment had better outcomes when children were younger, well motivated and did not have acanthosis nigricans.

AIM: This study evaluated the efficacy of a paediatric obesity treatment programme and explored the factors that contributed to the outcome. METHODS: We recorded the body mass index standard deviation scores (BMI SDS) of 654 children aged 2-18 years who were treated for obesity in 2005-2012 in three Finnish hospitals, one year before treatment and up to three years after treatment. The family-based multidisciplinary treatment included nutritional advice, exercise and behavioural counselling. The BMI SDS changes, and their contributors, were explored with mixed-model and logistic regression analyses. RESULTS: BMI SDS increased before baseline and decreased at six, 12 and 24 months (all p < 0.001) and 36 months (p = 0.005). Younger age (p < 0.001), higher BMI SDS at baseline (p = 0.001), motivation (p = 0.013), adherence to the protocol (p = 0.033) and lack of acanthosis nigricans (p < 0.001) improved the outcome. The BMI SDS of children aged 2-6 decreased best from baseline to 12 (-0.35), 24 (-0.58) and 36 months (-0.64) (all p < 0.001). CONCLUSION: Paediatric obesity treatment was most effective at a younger age. Good motivation and adherence contributed to favourable outcomes, while acanthosis nigricans was associated with a poor outcome.

Clinical, Genetic, and Biochemical Characteristics of Early-Onset Diabetes in the Finnish Population.

CONTEXT: Major advances have been made in the classification and genetics of monogenic diabetes in infancy. OBJECTIVE: The objective of the study was to characterize different forms of diabetes diagnosed during the first year of life. DESIGN: Patients diagnosed with diabetes before the age of 1 year in 10 Finnish hospitals from 1980 to 2014 were included. SETTING: The study was conducted at Kuopio University Hospital and University of Eastern Finland. PATIENTS: Patients were identified through diagnosis-based searches from hospital registries including 93 children, of whom 64 participated. INTERVENTIONS: DNA sample for sequencing, serum sample, and medical records interventions were included. MAIN OUTCOME MEASURES: Incidence of diabetes during the first year of life, sequencing results, human leukocyte antigen (HLA) genotypes, and islet autoantibodies were measured. RESULTS: The incidence of diabetes diagnosed during the first 12 months was 4.4/100 000/year. Three novel and 11 previously described mutations were found in 22 patients from 15 families in the KCNJ11, ABCC8, INS, GCK, FOXP, STAT3, and RFX6 genes. Positive islet autoantibodies were observed in 40.0% of the patients diagnosed during the first 0-6 months of life vs 70.8% of the patients diagnosed between ages of 7 to 12 months. A total of 85.7% of the patients carrying protective HLA genotypes were mutation-positive compared to 7.7% of the patients having high-risk genotypes (P = .001). CONCLUSIONS: Mutations in the K-ATP channel and INS genes were the most common cause of early diagnosed monogenic diabetes. After 6 months of age, patients with diabetes had high HLA risk genotypes and islet autoantibodies, reflecting the autoimmune character of diabetes in that age group.

Childhood obesity in specialist care--searching for a healthy obese child.

INTRODUCTION: One in three obese adults is classified as metabolically healthy, but there is less evidence in obese children. We studied the overall clinical presentation of Finnish obese children and the prevalence of cardiometabolic risk factors with child-specific cut-offs. MATERIAL AND METHODS: This is a cross-sectional register-based study of 2-18-year-old children (n = 900) evaluated for obesity in three hospitals in 2005-2012. Clinical and metabolic data were related to sex, age, puberty, and obesity grade and analyzed using chi-square and non-parametric tests. RESULTS: In 80% of cases at least one cardiovascular risk factor was present. Only 3% of subjects for whom complete metabolic data were available (n = 360) had no metabolic disorder. Systolic blood pressure was hypertensive in 50.2% and diastolic in 14.5% of the children. The youngest children had highest body mass index SD score. Obesity was more severe in boys than girls (p < 0.001). Hypertensive systolic blood pressure values (p = 0.012), prediabetes (p < 0.001), fatty liver (p < 0.001), and dyslipidemia (p = 0.025) were more prevalent in 15-18-year-old boys than girls. CONCLUSION: Most obese children in specialist care have cardiovascular risk factors; this indicates that earlier intervention is needed.

Functional characterization of novel loss-of-function mutations in the vasopressin type 2 receptor gene causing nephrogenic diabetes insipidus.

BACKGROUND: X-linked nephrogenic diabetes insipidus (NDI) is a rare polyuric disorder caused by inactivating mutations in the arginine vasopressin receptor Type 2 (AVPR2) gene. METHODS: NDI patients from six unrelated families were subjected to mutational analysis of the AVPR2 gene. In-depth in vitro characterization of novel AVPR2 mutants by a combination of functional and immunological techniques provided further insight into molecular mechanisms causing receptor dysfunction. RESULTS: Mutational analysis revealed four novel (A89P, G107R, Q174R, W208X) and three recurrent (V277A, R337X, ΔR247-G250) mutations within the AVPR2 gene. One family carried the missense mutation R337X and a 12-bp deletion (ΔR247-G250), corresponding to a fragment in the third intracellular loop (ICL3), which was not genetically linked to R337X. The functionally tested missense mutations A89P, G107R and Q174R led to reduced receptor cell surface expression in transfected COS-7 cells, most probably due to misfolding and intracellular retention, and consequently to reduction or loss of agonist-mediated cyclic adenosine monophosphate formation. Deletion of R247-G250 had no effect on receptor function in vitro. Comparison with other mammalian AVPR2 orthologs showed that this part of the ICL3 is structurally not conserved and, therefore, less relevant for receptor function. In contrast, all missense mutations (A89P, G107R, Q174R, V277A) affect receptor positions that were fully preserved during mammalian evolution. CONCLUSION: Our results provide valuable information about residues critical for AVPR2 folding, trafficking and function and proof that these mutations are responsible for causing NDI in the affected subjects.

Serum concentrations of adrenal steroids and their precursors as a measure of maturity of adrenocortical function in very premature newborns.

BACKGROUND: Relative adrenocortical insufficiency is often seen in sick premature newborns. As the human fetal adrenal cortex does not express the 3ß-hydroxysteroid dehydrogenase (3ß-HSD) enzyme before about 23 weeks of gestation, we hypothesized that this enzymatic step may be rate limiting in cortisol synthesis in premature infants of less than 28 weeks postmenstrual age at birth. METHODS: We measured cord, first day (D0) and median fourth day (D4) serum 17-OH-pregnenolone (17-OHPreg), 17-OH-progesterone (17-OHProg), 11-deoxycortisol, cortisol (F) and dehydroepiandrosterone sulphate concentrations and calculated the substrate/product ratios in 67 infants with gestational age 23.6-33.1 weeks. RESULTS: The mean 17-OHPreg/17-OHProg ratio as a marker of 3ß-HSD activity did not differ between the gestational age groups (gestational age <28 vs. ≥28 weeks: 0.40 vs. 0.48, p = 0.52 for cord, 3.1 vs. 2.4, p = 0.25 for D0, and 1.6 vs. 1.9, p = 0.62 for D4). In addition, the 17-OHPreg/17-OHProg ratio did not differ between the infants in the lowest F tertile compared to those in the highest F tertile group, and the serum 17-OHPreg and 17-OHProg concentrations were parallel with the respective F concentrations. CONCLUSION: We did not find evidence of significant immaturity in adrenal 3ß-HSD activity in preterm infants between 24 and 28 weeks of gestation.

Early hypoadrenalism in premature infants at risk for bronchopulmonary dysplasia or death.

AIM: To study the relationship between serum cortisol and dehydroepiandrosterone sulphate (DHEAS) concentrations and death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age in preterm infants. METHODS: Prospective measurement of cord, day of birth (D0) and day 4 (D4) serum cortisol and DHEAS concentrations and performance of low-dose (LD) ACTH tests in 89 preterm infants with gestational age <34 weeks at birth and in need of mechanical ventilation. RESULTS: Serum DHEAS levels correlated negatively with gestational age. At all sampling times, basal serum cortisol levels correlated positively with gestation-adjusted DHEAS levels (r = 0.39-0.46, p = 0.0032-<0.0001). The mean cord, D0 basal and stimulated cortisol, and cord and D0 DHEAS adjusted for gestational age were lower in the poor than good outcome infants (p < 0.02 for all). In the multiple logistic regression analyses, gestational age was the most significant factor affecting outcome, but low cord and D0 basal and stimulated cortisol and gestation-adjusted DHEAS levels also predicted poor outcome (OR 5.7-22; p = 0.049-0.014). CONCLUSIONS: Low cord and first day serum cortisol and DHEAS levels associated with poor outcome in preterm infants, which suggests general relative adrenocortical insufficiency in some premature newborns.

Circulating glucocorticoid bioactivity and serum cortisol concentrations in premature infants: the influence of exogenous glucocorticoids and clinical factors.

OBJECTIVE: Glucocorticoids are widely used before preterm delivery and in preterm infants may bear serious adverse effects. Better knowledge about the circulating glucocorticoid milieu after glucocorticoid treatment could improve treatment modalities. Therefore, we investigated the influence of exogenous glucocorticoids and clinical factors on serum cortisol (F) levels and circulating glucocorticoid bioactivity (GBA) in preterm infants. DESIGN: Eighty-nine infants (gestational age (GA) 23.6-33.1 weeks at birth) were enrolled in a prospective cohort study in two tertiary neonatal centres. METHODS: Cord, day of birth (D0), fourth day (D4) and 36 weeks postmenstrual age serum F and GBA levels were measured. RESULTS: The cord GBA was 5.8-fold and D0 GBA 2.3-fold higher in the infants exposed to antenatal steroids within 12 h before birth when compared with those unexposed or exposed >7 days before birth (95% CI 3.8-8.6; P<0.0001, and 1.8-3.0; P<0.0001 respectively). In the infants treated with early postnatal dexamethasone, D4 GBA was 1.7-fold (1.3-2.2; P<0.0005) higher when compared with levels in the infants without this treatment. Clinical factors indicating perinatal distress, such as Apgar scores <7 and low GA, were associated with higher cord, D0 and D4 serum F levels. CONCLUSIONS: Both ante- and postnatally administered glucocorticoids increase circulating GBA not attributable to endogenous F. Perinatal distress and preceding glucocorticoid treatment need to be taken into account when circulating glucocorticoid milieu is evaluated in preterm infants. The GBA assay may prove to be a useful instrument in the development of new glucocorticoid treatment strategies.

Early neonatal dexamethasone treatment for prevention of bronchopulmonary dysplasia. Randomised trial and meta-analysis evaluating the duration of dexamethasone therapy.

UNLABELLED: The aim of the aborted trial was to determine whether the short early dexamethasone (DX) given after the birth improves the early outcome. We also reviewed the evidence (meta-analysis) to determine whether the duration of early DX treatment influences the early outcome, particularly in terms of bronchopulmonary dysplasia (BPD). The participants of the randomised multicentre, double-blinded placebo-controlled trial had a birth weight 500-999 g, gestation < or = 31.0 weeks, and respiratory failure by the age of 4 h. The infants received either four doses of DX (0.25 mg/kg at 12 h intervals) or placebo. The meta-analysis was performed to determine the beneficial and adverse effects of early short (<96 h duration) versus early prolonged (>96 h) DX treatment. The trial was discontinued after 109 infants had been enrolled. There was a non-significant improvement in the outcome (survival without BPD, severe intracranial haemorrhage or periventricular leukomalacia; RR 1.27; 95% CI 0.87-1.85). The risks for gastrointestinal perforation and hyperglycaemia tended to increase. A total of 15 trials were included in the meta-analysis: 10 involved prolonged (i.e. >96 h; 1594 infants) and five short interventions (1069 infants). Early prolonged DX decreased the RR for BPD to 0.72 (95% CI 0.61-0.87), whereas early short DX course did not significantly decrease the risk (RR 0.82; 95% CI 0.64-1.05). Gastrointestinal haemorrhages and perforations were significantly increased only in the early prolonged DX group. CONCLUSION: The dosage and duration of early corticosteroid given to small premature infants influences the risk of the side-effects and the early outcome.