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Diabetes care in institutional settings is a significant challenge that affects the whole family as well as care workers and teachers. The present study is the ideation part of a rigorous development process in the KIds with Diabetes in School (KIDS) project. We have previously conducted a thorough three-part needs assessment in which we explored the problem area from the viewpoints of (1) municipal administrative staff, (2) preschool and school staff and (3) families. Based on the identified needs and to a great extent on the contents and shortcomings of existing guidelines, the objective of the present study is to explore and develop possible solutions and recommendations for addressing the challenges and problems. To meet this objective, we held comprehensive multistakeholder participatory workshops in each of the five Danish regions. Five main themes with multiple subthemes were identified as areas to be addressed: (1) training and knowledge, (2) communication and collaboration, (3) the designated contact/support person, (4) national guidelines, and (5) the Diabetes Coordinator. Our findings demonstrate that communicative structures and dynamics are at the very heart of the identified problems and challenges and that the possible solutions should revolve around improving existing structures and highlighting the importance of constantly working on understanding and developing communication strategies. We propose a set of recommendations for practice based on these communicative needs.

Competing Interests: Declaration of competing interest None.

Managing diabetes is complicated for many children. It often requires support from an adult during the school day. In Denmark, most children spend 30-35 h a week at school. Nevertheless, diabetes management in schools remains largely uninvestigated. This study aimed to examine the characteristics and organization of diabetes management in Danish primary schools from the personnel's perspective. All primary schools in Denmark were invited to participate in the study ( n = 2129), and 525 schools were included. A questionnaire was constructed and sent by email. Questionnaire data are presented in the descriptive statistics and compared with the ISPAD guidelines. According to 77.2% of respondents, school personnel had received training in diabetes management, and 78.5% of the schools had at least one person available for diabetes support every day. Respondents felt prepared to help the students with counting carbohydrates (38.9%), dosing insulin (39.1%), and helping the students during high (52.1%) or low (60.3%) blood sugar levels, insulin chock (35.2%), or during activities (36.3%). Yet, diabetes management was a challenging task. Only 61.7% had an action plan for diabetes management, 37.4% had face-to-face information meetings with the parents, and 55.1% of respondents reported having sufficient time to cooperate with the parents.

Diabetes care during institutional hours is a major challenge affecting the whole family. The aim of this study was to highlight challenges and potentials regarding municipal support in relation to diabetes care of children in school, kindergarten, and daycare. The dataset consists of 80 semi-structured online interviews with 121 municipal employees from 74 (of 98) municipalities in Denmark. Data were analysed using qualitative content analysis. The analysis produced four main themes: (1) Institutional staff initially feel insecure about diabetes care responsibilities, (2) There is a high degree of parental involvement and responsibilities during institutional hours, (3) The roles of health employees vary, and (4) Fluctuating allocation of special needs assistants (SNAs) creates challenges. The findings of this nationwide qualitative study show that, even though Denmark guarantees, by law, the child's right to support in diabetes self-care in school and childcare institutions, diabetes management in Denmark still needs to be improved, with a view to ensuring equal support for all children with diabetes.

The adipokines adiponectin and leptin play key roles in human metabolic regulation and have gained great attention as biomarkers for various metabolic pathologies. Though, pediatric reference values are few and needed. This study aims to establish age- and sex-specific adipokine reference percentiles based on healthy Danish school children. Further, it elucidates sex-specific differences in associations between z-scores of examined adipokines and metabolic variables. Serum adiponectin and serum leptin from 853 observations of healthy Danish schoolchildren aged 8-17 years (median 10.0) were quantified by immunoassays. Age- and sex-specific adipokine reference percentiles were calculated cross-sectionally using the LMS method, and adipokine z-scores were calculated from the fitted model. Multiple linear regression models were used to examine sex-specific differences in associations between adipokine z-scores and various metabolic variables. Girls had a higher median value of adiponectin (11.31 vs. 10.65 μg/mL, p  < .001) and leptin (2.30 vs. 1.00 ng/mL, p  < .001) and a lower median value of adiponectin/leptin ratio (4.64 vs. 10.76, p  < .001) compared to boys. Sex-specific differences were found in associations between adiponectin z-score and HDL ( p  = .010), between leptin z-score and waist circumference z-score ( p  = .027) and LDL ( p  = .048), and between adiponectin/leptin ratio z-scores and waist circumference z-score ( p  = .044) and LDL ( p  = .040). Reference percentiles of adiponectin, leptin, and adiponectin/leptin ratio are presented in this paper. To our knowledge, this study is the first to demonstrate sex-specific differences in associations between adipokine z-scores and waist circumference z-score and lipids, respectively in healthy children and adolescents.

Objective: The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY)., Design: We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020)., Methods: Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis., Results: A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%)., Conclusions: We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

Vitamin D supplementation in infancy is recommended to prevent rickets. At the population level, its effects on bone mineralisation are largely unknown. We aimed to explore whether adherence to national vitamin D supplementation guidelines (10 µg/d up to the age of 2 years), supplementation at the ages of 5 and 7 years, and serum 25-hydroxyvitamin D (s-25(OH)D) at various time points associated with bone mineral density (BMD) at the age of 7 years in the Odense Child Cohort, Denmark (n 1194). High adherence was defined as supplementation with 10 µg of vitamin D 6-7 times per week during ≥80 % of the observation time. s-25(OH)D was analysed using LC-MS/MS. Total-body-less-head (TBLH) BMD was measured by dual-energy X-ray absorptiometry. At the median age of 18·1 months, 53·9 % (n 475/881) reported high adherence. The median s-25(OH)D was 64·7, 78·8, 46·0 and 71·8 nmol/l in early pregnancy, late pregnancy, cord blood and at 5 years, respectively. The mean TBLH BMD at the median age of 7·1 years was 0·613 (SD 0·049) g/cm2 (z-score +0·363 (SD 0·824)). In adjusted analyses, vitamin D supplementation up to 18 months, and at 5 and 7 years, was not associated with TBLH BMD. Similarly, no robust associations were found between TBLH BMD and s-25(OH)D at any time point. No associations were found for TBLH bone mineral concentration or bone area. In this population with relatively high s-25(OH)D concentrations, no consistent associations were found between adherence to vitamin D supplementation recommendations or vitamin D status in pregnancy or childhood, and bone mineralisation at the age of 7 years.

Purpose: Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents., Method: BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8-18 years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded., Results: The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. β-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI., Conclusion: RI for β-CTX, PINP, OC and bone ALP varies with age and sex. β-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Patients with type 1 diabetes has an increased risk of fracture. We wished to evaluate estimated bone strength in children and adolescents with type 1 diabetes and assess peripheral bone geometry, volumetric bone mineral density (vBMD) and microarchitecture., Research Design and Methods: In a cross-sectional study, high-resolution peripheral quantitative CT (HR-pQCT) was performed of the radius and tibia in 84 children with type 1 diabetes and 55 healthy sibling controls. Estimated bone strength was assessed using a microfinite element analysis solver. Multivariate regression analyses were performed adjusting for age, sex, height and body mass index., Results: The median age was 13.0 years in the diabetes group vs 11.5 years in healthy sibling controls. The median (range) diabetes duration was 4.2 (0.4-15.9) years; median (range) latest year Hb1Ac was 7.8 (5.9-11.8) % (61.8 (41-106) mmol/mol). In adjusted analyses, patients with type 1 diabetes had reduced estimated bone strength in both radius, β -390.6 (-621.2 to -159.9) N, p=0.001, and tibia, β -891.9 (-1321 to -462.9) N, p<0.001. In the radius and tibia, children with type 1 diabetes had reduced cortical area, trabecular vBMD, trabecular number and trabecular bone volume fraction and increased trabecular inhomogeneity, adjusted p<0.05 for all. Latest year HbA1c was negatively correlated with bone microarchitecture (radius and tibia), trabecular vBMD and estimated bone strength (tibia)., Conclusion: Children with type 1 diabetes had reduced estimated bone strength. This reduced bone strength could partly be explained by reduced trabecular bone mineral density, adverse microarchitecture and reduced cortical area. We also found increasing latest year HbA1c to be associated with several adverse changes in bone parameters. HR-pQCT holds potential to identify early adverse bone changes and to explain the increased fracture risk in young patients with type 1 diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Unexplained or idiopathic ketotic hypoglycemia (KH) is the most common type of hypoglycemia in children. The diagnosis is based on the exclusion of routine hormonal and metabolic causes of hypoglycemia. We aimed to identify novel genes that cause KH, as this may lead to a more targeted treatment. Deep phenotyping of ten preschool age at onset KH patients (boys, n = 5; girls, n = 5) was performed followed by trio exome sequencing and comprehensive bioinformatics analysis. Data analysis revealed four novel candidate genes: (1) NCOR1 in a patient with KH, iron deficiency and loose stools; (2) IGF2BP1 in a proband with KH, short stature and delayed bone age; (3) SLC5A2 in a proband with KH, intermittent glucosuria and extremely elevated p-GLP-1; and (4) NEK11 in a proband with ketotic hypoglycemia and liver affliction. These genes are associated with different metabolic processes, such as gluconeogenesis, translational regulation, and glucose transport. In conclusion, WES identified DNA variants in four different genes as potential novel causes of IKH, suggesting that IKH is a heterogeneous disorder that can be split into several novel diseases: NCOR1-KH, IGF2BP1-KH, SGLT2-KH or familial renal glucosuria KH, and NEK11-KH. Precision medicine treatment based on exome sequencing may lead to advances in the management of IKH.

Background/objective: Fracture risk is increased in patients with type 1 diabetes. We aimed to evaluate bone mineral density (BMD) and to identify risk factors associated to lower BMD in Danish children and adolescents with type 1 diabetes., Methods: In this cross-sectional study BMD Z-score were determined by dual-energy X-ray absorptiometry (DXA) from a cohort of otherwise healthy children and adolescents with type 1 diabetes. Puberty Tanner stage, hemoglobin A1c (HbA1c), disease duration, and age at diabetes onset were investigated for associations to DXA results., Results: We included 85 patients, 39 girls, 46 boys, with a median (range) age of 13.2 (6-17) years; disease duration 4.2 (0.4-15.9) years; HbA1c of the last year 61.8 (41-106) mmol/mol. Our patients were taller and heavier than the background population. When adjusted for increased height SD and body mass index SD, no overall difference in BMD Z-score was found. When stratified by sex, boys had significantly increased adjusted mean BMD Z-score, 0.38 (95% confidence interval [CI]: 0.13;0.62), girls; -0.27 (95% CI: -0.53;0.00). For the whole cohort, a negative correlation between mean latest year HbA1c and BMD Z-score was found, adjusted ß -0.019 (95%CI: -0.034;-0.004, P = 0.01). Poor glycemic control (HbA1c > 58 mmol/mol [7.5%]) within the latest year was likewise negatively correlated with BMD Z-score, adjusted ß -0.35 (95%CI: -0.69;-0.014, P = 0.04)., Conclusions: Our study suggests that elevated blood glucose has a negative effect on the bones already before adulthood in patients with type 1 diabetes, although no signs of osteoporosis were identified by DXA., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Insulin resistance may exert a negative influence on bone mass in childhood and adolescence. The objective was to assess the association between insulin resistance and total body less head (TBLH) bone mineral content (BMC) and to investigate whether body composition, physical activity or osteocalcin levels may influence this association., Methods: A longitudinal study with follow-up over more than 6 years was performed and included 562 apparently healthy participants with a mean age of 9.6 years at baseline. Participants underwent DXA scanning at baseline. At the two follow-ups, participants had performed another DXA scanning, had blood samples taken for fasting insulin, glucose and osteocalcin and had physical activity measured with an accelerometer. HOMA-IR was calculated as an index of insulin resistance., Results: HOMA-IR was negatively associated with TBLH BMC in boys at follow-ups (β = -31.4, p < 0.001) after adjustment for maturity, height, bone area, and baseline level of TBLH BMC. The negative association remained almost unchanged after further adjustments for body composition and physical activity. No association between HOMA-IR and TBLH BMC was found in girls., Conclusion: Insulin resistance may be detrimental for bone development through puberty in boys independent of body composition and the level of physical activity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This longitudinal study examined associations of bone mass with physical activity and vitamin D level over more than 6 years through puberty. A total of 663 participants (320 boys) with mean age 9.6 years at baseline (10-17 years at follow-up), underwent dual energy X-ray absorptiometry, anthropometry and blood samples for vitamin D at least twice during the study period (with three possible time-points). Physical activity was assessed using accelerometers at follow-up. A positive association was found between percent time spent at vigorous physical activity and total-body less head bone mineral content (β = 5.8, p = 0.002). The magnitude of this association increased with maturational development; thus physical activity may have a greater influence on bone mass in the more mature participants. The vitamin D levels were also positively associated with bone mass. A high degree of tracking was observed with changes in anthropometric Z scores predictive of deviation from tracking. No environmental factor predicted deviation from tracking.

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through G q/11 and G i/o to stimulate cytosolic calcium (Ca 2+ i ) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca 2+ i responses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSR R680G in HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca 2+ i responses. Moreover, this gain of function in MAPK activity occurred independently of G q/11 and G i/o and was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg 680 and Glu 767 , which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg 680 -Glu 767 salt bridge in mediating signaling bias., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Overweight, physical inactivity and sedentary behaviour have become increasing problems during the past decade. Increased sedentary behaviour may change the body composition (BC) by increasing the fat mass relative to the lean mass (LM). These changes may influence bone health to describe how anthropometry and BC predict the development of the bone accruement. The longitudinal study is a part of The CHAMPS study-DK. Children were DXA scanned at baseline and at 2-year follow-up. BC (LM, BF %) and BMC, BMD and BA were measured. The relationship between bone traits, anthropometry and BC was analysed by multilevel regression analyses. Of the invited children, 742/800 (93%) accepted to participate. Of these, 682/742 (92%) participated at follow-up. Mean (range) of age at baseline was 9.5 years (7.7-12.1). Height, BMI, LM and BF % predicted bone mineral accrual and bone size positively and independently. Height and BMI are both positive predictors of bone accruement. LM is a more precise predictor of bone traits than BF % in both genders. The effects of height and BMI and LM on bone accruement are nearly identical in the two genders, while changes in BF % have different but positive effects on bone accretion in both boys and girls.

Objective: To evaluate the effect of a school based physical education (PE) program and the amount of leisure time sport (LTS) on children's bone health and to examine if LTS influences the impact of school type on children's bone health., Methods: Children attending "sports" schools (6 × 45 min PE lessons per week) were compared to children at "traditional" schools (2 × 45 min of PE lessons per week) in Svendborg, Denmark. Whole-body DXA scans were performed at baseline (2008) and at a two-year follow-up (2010). Bone mineral content (BMC), bone mineral density (BMD), and bone area (BA) were measured. Multilevel regression analyses examined the impact of school type and LTS participation on bone., Results: 742/800 (93%) invited children accepted to participate. 682/742 (92%) participated at two-year follow-up. Mean (SD) age was 9.5 years (0.9) at baseline. A positive association between LTS and BMC, BMD (p<0.001) and for BA (p<0.05) (total body less head (TBLH) and lower limb (LL)) was found. All effects regarding school type were insignificant., Conclusion: A positive impact of attending LTS on bone traits was found. There was no effect on BMC, BMD and BA (TBLH, and LL) for children attending sports schools compared to traditional schools., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Studies indicate genetic and lifestyle factors can contribute to optimal bone development. In particular, the intensity level of physical activity may have an impact on bone health. This study aims to assess the relationship between physical activity at different intensities and Bone Mineral Content (BMC), Bone Mineral Density (BMD) and Bone Area (BA) accretion., Methods: This longitudinal study is a part of The CHAMPS study-DK. Whole-body DXA scans were performed at baseline and after two years follows up. BMC, BMD, and BA were measured. The total body less head (TBLH) values were used. Physical activity (PA) was recorded by accelerometers (ActiGraph, model GT3X). Percentages of different PA intensity levels were calculated and log odds of two intensity levels of activity relative to the third level were calculated. Multilevel regression analyses were used to assess the relationship between the categories of physical activity and bone traits., Results: Of 800 invited children, 742 (93%) accepted to participate. Of these, 682/742 (92%) participated at follow up. Complete datasets were obtained in 602/742 (81%) children. Mean (range) of age was 11.5 years (9.7-13.9). PA at different intensity levels was for boys and girls respectively, sedentary 62% and 64%, low 29% for both genders and moderate to high 9% and 7% of the total time. Mean (range) BMC, BMD, and BA was 1179 g (563-2326), 0.84 g/cm2 (0.64-1.15) and 1393 cm2 (851-2164), respectively. Valid accelerometer data were obtained for a mean of 6.1 days, 13 hours per day., Conclusions: There 7was a positive relationship between the log odds of moderate to high-level PA versus low level activity and BMC, BMD and BA. Children with an increased proportion of time in moderate to high-level activity as opposed to sedentary and low-level activity achieved positive effects on BMC, BMD and BA.

Objective: End-point bioassays based on thymidine or sulfate incorporation have demonstrated that glucocorticoid (GC) treatment inhibits serum IGF1 action, but the mechanism is unknown as serum IGF1 concentrations have been reported to either increase or remain unchanged., Aim: To investigate whether GC treatment affects the ability of serum to activate the IGF1 receptor (IGF1R) in vitro (i.e. bioactive IGF1), using a specific cell-based IGF1 kinase receptor activation assay., Subjects and Methods: Twenty children with stable asthma (age 7.7-13.8 years) treated for 1 week with 5 mg prednisolone in a randomized, double-blind, placebo-controlled crossover study. Non-fasting serum samples were collected in the afternoon after each 7-day period and assayed for bioactive IGF1, free IGF1, total IGFs, IGF-binding proteins (IGFBPs), and insulin., Results: Prednisolone treatment reduced IGF1 bioactivity by 12.6% from 2.22±0.18 to 1.94±0.15 μg/l (P=0.01) compared with placebo. In contrast, no changes were observed for (μg/l; placebo vs prednisolone) total IGF1 (215±27 vs 212±24), free IGF1 (1.50±0.16 vs 1.43±0.17), total IGF2 (815±26 vs 800±31), IGFBP3 (3140±101 vs 3107±95), IGFBP2 (238±21 vs 220±19), IGFBP1 (32±6 vs 42±10), or IGFBP1-bound IGF1 (24±5 vs 26±7). Insulin remained unchanged as did IGFBP levels as estimated by western ligand blotting. Prednisolone had no direct effects on IGF1R phosphorylation., Conclusions: Our study gives evidence that GC treatment induces a circulating substance that is able to inhibit IGF1R activation in vitro without affecting circulating free or total IGF1. This may be one of the mechanisms by which GC inhibits IGF1 action in vivo. However, the nature of this circulating substance remains to be identified.

Background/Aims. Glucocorticoids may have adverse effects on carbohydrate and lipid metabolism. The present study was conducted to investigate possible effects on carbohydrate and lipid metabolism of inhaled and oral glucocorticoids in children with asthma. Methods. Two randomised controlled trials with blinded crossover designs were performed. Active treatment was 400  μ g inhaled budesonide or 5 mg prednisolone orally daily during one week. The budesonide trial included 17 and the prednisolone trial 20 school children. Serum fructosamine, total cholesterol and high-density lipoprotein were assessed. Results. Serum fructosamine was increased during active treatment (prednisolone 252.3  μ M versus placebo 247.3  μ M; P = 0.03 and budesonide 228.1  μ M versus no treatment 223.1  μ M; P = 0.02). Total cholesterol and high-density lipoprotein were not statistically significantly increased. Conclusion. Short-term treatment with oral prednisolone and inhaled budesonide may adversely affect mean blood glucose concentration. Possible long-term consequences require further investigations.

Malignant infantile osteopetrosis (MIOP) is a hereditary bone disorder caused by osteoclastic dysfunction. Within the first year of life affected children present with recurrent infections, vision impairment, failure to thrive, bone marrow failure, and at later stages neurological deficits and ultimately death. Bone marrow transplant (BMT) is the only curative treatment. We present a patient with MIOP, who showed the first symptoms at three weeks of age, and the disease was diagnosed at 11 months of age. The boy had a successful BMT after which the delayed psychomotor development improved.

Background: Knemometry studies of growth suppressive effects of inhaled glucocorticoids in children with asthma usually allow participating children to use concomitant inhaled beta2-agonists. Systemic beta2-agonists, however, have been found to suppress growth hormone secretion and this has caused concern about a possible confounding effect of inhaled beta2-agonists on results of growth studies of exogenous glucocorticoids., Aim: The study evaluated whether inhaled salbutamol adversely affects short-term growth., Subjects and Methods: Fifteen children aged 6-12 years with mild asthma were enrolled in a single-blind, randomized crossover study with two 2-week treatment periods and a 1-week run-in. During the active period treatment dry powder salbutamol (Ventoline Diskhaler) 200 microg was inhaled three times a day. During the comparative period no treatment was given. Knemometry of the right lower leg was performed on the first and the last day of each period., Results: Mean lower leg growth rates (SEM) during no-treatment and salbutamol periods were 0.35 (0.06) and 0.42 (0.07) mm per week, respectively (P = 0.35, t = -0.98, 95% CI: 0.25-0.93 mm per week)., Conclusions: Inhaled salbutamol 200 microg three times daily does not suppress short-term growth in asthmatic children. Inhaled beta2-agonists in equipotent doses and regimens can be safely used in short-term knemometric growth studies of exogenous glucocorticoids without any risk of confounding the results.

Background: The growth-suppressive effect of systemic glucocorticoids in children is well established, however, recovery of growth after withdrawal of short-term treatment in school-age children has not been evaluated., Objective: To assess short-term growth after withdrawal of systemic glucocorticoids., Methods: A post-hoc analysis of data from a double-blind lower leg growth trial which compared 5 mg prednisolone once daily in the evening with placebo was performed. The study consisted of run-in, treatment, wash-out and run-out periods of 1 week duration. In 10 children with asthma (mean age 11 years) lower leg growth measured with the knemometer could be studied up to 3 weeks after withdrawal of prednisolone., Results: Mean (SEM) lower leg growth rates during run-in, prednisolone treatment and the first, second and third weeks after withdrawal of prednisolone were 0.48 (0.15), -0.27 (0.20), 0.53 (0.19), 0.72 (0.16) and 0.66 (0.14) mm/week, p < 0.001. Mean growth rates during run-in and the first, second and third weeks after withdrawal of prednisolone did not vary, p = 0.68., Conclusion: Recovery of suppressed lower leg growth rates occurs within a week after withdrawal of exogenous glucocorticoids., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: High-frequency ultrasound of the skin has recently been introduced for assessment of systemic effects in the cutis and subcutis of oral and inhaled glucocorticoids in children. However, the use of high-frequency skin ultrasound in clinical trials is invalidated because important methodological aspects have not been addressed. The aim of the present study was to evaluate inter- and intraobserver, day to day and diurnal variations of measurement of thickness of cutis and subcutis, and the fraction of low echogenic pixels (fLEP) in the cutis and, furthermore, to assess effects of exercise on the cutis and subcutis and variations in subcutaneous thickness between anatomical locations in children with a high-frequency B-mode ultrasound scanning device., Methods: Three studies were conducted, each including 10 healthy prepubertal children. High-frequency skin ultrasound was performed with the 20 MHz Dermascan C (Cortex Technology, Hadsund, Denmark). In study 1, the same observer performed five consecutive scannings to assess intraobserver variations. In study two different observers performed scannings at 2 h intervals between 08:00 and 20:00 h, whereby interobserver and diurnal variations were assessed. In study 3, the same observer performed scannings in different anatomical locations on five consecutive days, and on one of these days before and after exercise. Thus day-to-day variations and the effect of exercise were assessed., Results: Low inter- and intraobserver variations were found on assessment of the thickness of cutis and subcutis, whereas high variations were found on evaluation of the dermal water content. Diurnal variations were absent, and day-to-day variations were low. Exercise caused significant increases in the thickness of cutis and subcutis on the thigh., Conclusion: Low inter- and intraobserver variations make high-frequency ultrasound a precise and reliable tool for assessment of the cutaneous and subcutaneous thickness in children. In future trials, repetitive scannings need not to be performed at the same time of the day, whereas strenuous physical activity should be avoided on days of examination.

Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover. We utilized a randomized, double-blind, two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration. The setting was an Outpatient clinic in a secondary referral center. Subjects included 14 boys and 3 girls with a mean age of 11.7 (range, 6.1-14.4) years. Interventions included 15 microg (600 IU) 25-OH-vitamin D (cholecalciferol) in one tablet ABCDin(R) once daily in the morning. Primary outcome measures were: lower leg growth rate, serum osteocalcin, and serum markers of type I collagen turnover, i.e., the amino terminal propeptide of type I procollagen (PINP), the carboxy terminal propeptide of type I procollagen (PICP) (formation markers), and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) (degradation markers). Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment (NS). Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment, respectively, PINP 574 and 565 microg/l, PICP 381 and 382 microg/l, and ICTP 11.5 and 11.1 microg/l, respectively (NS). Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l, respectively (P < 0.001). There were no statistically significant differences in measures of pulmonary function. In conclusion, administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily., (Copyright 2003 Wiley-Liss, Inc.)

Objective: To assess the thickness of the cutis and subcutis in children with prednisolone-induced knemometric growth suppression., Design: A double blind, placebo-controlled crossover trial with two 7-day treatment periods., Patients: Twenty children with asthma aged 7.7 to 13.8 (mean 10.4) years., Interventions: 5 mg prednisolone/day., Outcome Measures: Lower leg growth rate, thickness of cutis and subcutis and the fraction of low echogenic pixels determined by ultrasound., Results: Mean lower leg growth rate was -0.23 during prednisolone, 0.58 mm/week during placebo treatment (p < 0.01). Mean total thickness of cutis and subcutis over the knee was reduced by 0.28 during prednisolone, increased by 0.07 mm/week during placebo treatment (p = 0.04). Lower leg growth rate was positively correlated to changes in thickness of cutis and subcutis (p = 0.04; r = 0.31)., Conclusions: Reductions in thickness of cutis and subcutis may account for some of the lower leg growth suppression caused by systemic glucocorticoids.

Long-term glucocorticoid excess decreases peripheral and increases abdominal subcutaneous thickness. Short-term prednisolone treatment is used in the treatment of many acute and chronic conditions in children. The aim of the present study was to elucidate if changes in thickness of cutis, subcutis, or dermal water content may be induced by short-term prednisolone treatment in children. Twenty children with asthma aged 7.7-13.8 years were included in a double-blind, randomized, placebo-controlled crossover trial. Active treatment was 5mg prednisolone daily. Treatment, run-in, and wash-out periods were 1 week. On days 1 and 7 of each treatment period, 20 MHz ultrasound scanning of the skin was performed on the thigh, forearm, and abdomen. Prednisolone treatment was associated with decreases in the total thickness of the cutis and subcutis in the thigh (0.28 mm) and forearm (0.15 mm), and an increase in the abdomen (0.23 mm). During placebo treatment the thickness was increased in the thigh (0.07 mm) and abdomen (0.05 mm), and reduced in the forearm (0.03 mm). The differences between prednisolone and placebo treatment were statistically significant in the thigh (P=0.04). The increase in thickness in the abdomen during prednisolone treatment was statistically significantly different from the reductions in the thigh (P=0.03) and forearm (P=0.05). There were no statistically significant differences in the dermal thickness or water content during prednisolone treatment compared to placebo.Short-term treatment with 5mg prednisolone daily may cause differential effects in peripheral and abdominal subcutaneous thickness in children.

Background: The deceleration of longitudinal growth in children during winter occurs simultaneously with a decrease in the number of daylight hours and a reduction in vitamin D status. Due to worries about deleterious effects on bone of a relative insufficiency, vitamin D supplementation to healthy children has been suggested., Aim: To see whether supplementation of vitamin D to healthy children during winter affects seasonal growth., Subjects and Methods: Twelve girls and eight boys aged 6.2-13.7 (mean 9.8) years, all healthy, were enrolled in a double-blind, randomized, placebo-controlled cross-over study with two 4-week treatment periods and 2-week run-in and wash-out periods. Vitamin D(3) 600 IU was given in one tablet ABCDin daily. Knemometry of the right lower leg was performed on the first and last day of each period., Results: Lower leg growth rates (mean +/- SEM) during placebo and vitamin D(3) administration were identical: 0.28 +/- 0.04 mm per week (p = 0.94, t = 0.1, 95% CI: - 0.12-0.13 mm per week)., Conclusion: Supplementation with vitamin D(3) 600 IU day(-1) to healthy children during winter may not improve seasonal growth. Therefore, supplementation may not be recommended on the grounds of concerns about growth; however firm conclusions await randomized long-term studies.