Role of glucocorticoid metabolism in childhood obesity-associated hypertension.

Objective: Childhood obesity is associated with alterations in hypothalamus-pituitary-adrenal axis activity. We tested the hypothesis that multiple alterations in the metabolism of glucocorticoids are required for the development of hypertension in children who become overweight. Methods: Spot urine for targeted gas chromatography-mass spectrometry steroid metabolome analysis was collected from (1) overweight/hypertensive children (n = 38), (2) overweight/non-hypertensive children (n = 83), and (3) non-overweight/non-hypertensive children (n = 56). Results: The mean (± s.d.) age of participants was 10.4 ± 3.4 years, and 53% of them were male. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3 (869 (interquartile range: 631-1352) vs 839 (609-1123) vs 608 (439-834) µg/mmol creatinine × m2 body surface area, P < 0.01, for the sum of cortisol metabolites), and group 1 had a higher excretion rate of naive cortisol than group 3. Furthermore, groups differed in cortisol metabolism, in particular in the activities of 11ß-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), 5α-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3). Discussion: The sequence of events leading to obesity-associated hypertension in children may involve an increase in the production of glucocorticoids, downregulation of 11ß-hydroxysteroid dehydrogenase type 1 activity, and upregulation of 5α-reductase activity, along with a decrease in CYP3A4 activity and an increase in bioavailable cortisol.

Health needs of refugee children identified on arrival in reception countries: a systematic review and meta-analysis.

BACKGROUND: The worldwide number of refugees has considerably increased due to ongoing wars, national instability, political persecution and food insecurity. In Europe, about one-third of all refugees are children, an increasing number of which are travelling alone. There are often no systematic medical health assessments for these refugee children on entry in reception countries despite the fact that they are recognised as an at-risk population due to increased burden of physical and mental health conditions. We aimed to perform a systematic review of the literature to describe the health status of refugee children on entering reception countries. METHODS: A systematic search of published literature was conducted using the terms refugee, immigrant or migrant, medical or health, and screening. RESULTS: Of the 3487 potentially relevant papers, 53 population-based studies were included in this review. This systematic review showed that refugee children exhibit high estimated prevalence rates for anaemia (14%), haemoglobinopathies (4%), chronic hepatitis B (3%), latent tuberculosis infection (11%) and vitamin D deficiency (45%) on entry in reception countries. Approximately one-third of refugee children had intestinal infection. Nutritional problems ranged from wasting and stunting to obesity. CONCLUSIONS: Refugee children entering reception countries should receive comprehensive health assessments based on the outcomes of this systematic review, national budgets, cost-effectiveness and personal factors of the refugees. The health assessment should be tailored to individual child health needs depending on preflight, flight and postarrival conditions.A paradigm shift that places focus on child health and development will help this vulnerable group of children integrate into their new environments. PROSPERO REGISTRATION NUMBER: 122561.

Is mid-upper arm circumference in Dutch children useful in identifying obesity?

BACKGROUND: Mid-upper arm circumference (MUAC) is suggested as being a valid measure in detecting overweight/obesity in children and adolescents, due to the strong relation with weight. We examined this relation and compared MUAC to body mass index (BMI) according to the International Obesity Task Force (IOTF) in children. METHODS: Anthropometric data including MUAC were collected in 2009 by trained healthcare professionals in the context of the fifth Dutch Nationwide Growth Study, in a sample of 6167 children (2891 boys and 3276 girls) aged 2-18 years of Dutch origin. We propose MUAC SDS cut-off values for overweight and obesity, and compared MUAC with BMI IOTF in sex-specific and age-specific categories (2-5, 6-11, 12-18 years). RESULTS: The area under the curve is used as a measure of diagnostic accuracy; the explained variance (R²) is good to excellent (0.88-0.94). Sensitivity ranges from 51.8% to 95.3% and specificity from 71.4% to 93.8%. Across age and gender groups, 65.1% to 89.0% participants are classified by both MUAC and BMI as normal weight, overweight or obese. We constructed three equations to predict weight using MUAC, with small differences between observed and predicted weight with an explained variance ranging from 0.88 to 0.94. CONCLUSIONS: Compared with BMI, MUAC is a valid measure for detecting overweight and obesity and thus a good alternative for BMI. When weight has to be estimated, it can be accurately predicted using MUAC. Based on our observations, we recommend developing diagrams with international (IOTF) cut-offs for MUAC SDS similar to BMI.

Stabilization of the obesity epidemic and increasing thinness in children in Caribbean Bonaire.

BACKGROUND: In 2008, the prevalence of overweight and obesity among children in Bonaire was twice as high as the prevalence in northern Europe but comparable to that of other Caribbean islands and the United States. The aim of this study was to examine change in the body mass index status of children in Bonaire and report children's energy balance-related behaviours (EBRB) in 2015. METHODS: Two school-based cross sectional surveys of children age 4-14 years were conducted in 2008 and 2015. Height (m) and weight (kg) were measured, body mass index (BMI) calculated and children's BMI categorised according to the International Obesity Task Force criteria. In 2015, children age 10-14 years completed a questionnaire on EBRB and responses were compared between non-overweight/obese children and overweight/obese children. RESULTS: In total 2117 children age 4-14 years participated (92.4% response rate). The prevalence of thinness significantly increased between 2008 and 2015 (adjusted OR 1.5 95% CI: 1.2-1.8). There were no other significant differences in children's weight status between survey years. One quarter of children (25.4%) were overweight/obese in 2015. There were no significant differences in EBRB between non-overweight/obese and overweight/obese children in 2015. Few children met recommendations for EBRB. CONCLUSIONS: The prevalence of overweight/obesity in children in Bonaire did not significantly change between 2008 and 2015 and remained high. However, the prevalence of thinness has significantly increased. Interventions to improve children's current EBRB are required.

Is There an Association Between Cortisol and Hypertension in Overweight or Obese Children?

OBJECTIVE: The precise mechanisms behind the development of hypertension in overweight or obese children are not yet completely understood. Alterations in hypothalamic-pituitary-adrenal axis activity may play a role. We aimed to investigate the association between cortisol parameters and hypertension in overweight or obese children. METHODS: Random urine (n=180) and early-morning saliva samples (n=126) for assessment of cortisol and cortisone were collected from 1) hypertensive overweight children (n=50), 2) normotensive overweight children (n=145), and 3) normotensive non-overweight children (n=75). RESULTS: The age of participants was 10.4±3.3 years and 53% were boys. The urinary cortisol-to-cortisone ratio [ß 1.11, 95% confidence interval (CI) 1.05-1.19] as well as urinary cortisol/creatinine (ß 1.38, 95% CI 1.09-1.54), and cortisone/creatinine ratios (ß 1.26, 95% CI 1.17-1.36) were significantly higher in overweight or obese than in non-overweight children. After adjusting for body mass index-standard deviation score and urinary cortisone/creatinine ratio, but not cortisol/creatinine ratio, was significantly associated with presence of hypertension (ß 1.12, 95% CI 1.02-1.23). Salivary cortisol and cortisone levels were significantly lower in overweight or obese than in non-overweight children (ß -4.67, 95% CI -8.19- -1.15, and ß 0.89, 95% CI 0.80-0.97 respectively). There were no significant differences in cortisol parameters between hypertensive and normotensive overweight or obese children. CONCLUSION: This study provided further evidence for an increased cortisol production rate with decreased renal 11ß-hydroxysteroid dehydrogenase 2 activity and flattening of early-morning peak cortisol and cortisone in overweight or obese children. However, there were no significant differences in cortisol parameters between hypertensive and normotensive overweight and obese children.

Screening, diagnosis and treatment of hypertension in obese children: an international policy comparison.

Hypertension in obese children may require a different diagnostic and treatment approach from that for children with secondary hypertension, yet there is neither consensus nor a clear guideline. The aim of this study was to assess how obese children with hypertension are currently diagnosed and treated by paediatric nephrologists, what obstacles exist and what can be improved. In the period May-November 2014, an online questionnaire was sent to all members of the European Society for Paediatric Nephrology (n = 2148). Questions focused on current practices and obstacles regarding screening, diagnosis and treatment of hypertension in obese children. A total of 214 paediatric nephrologists responded. Although nearly 100 % agreed that screening of obese children for hypertension is indicated, it was current practice in only 56 % of participating countries; 88 % of respondents diagnosed hypertension with 24-h ambulatory blood pressure measurement. Diagnostics used to rule out causes or consequences of hypertension varied among the respondents; they included, in particular, the use of serum renin/aldosterone, urine sodium/potassium, and dimercaptosuccinic acid scan. Concerning treatment, 45 % of respondents preferred to start treatment with a lifestyle program, 2 % with antihypertensive medication, and 40 % with both. For 73 % of respondents, angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers were the drugs of first choice. The findings of this study emphasize the urgent need for an international guideline for screening, diagnosis and treatment of hypertension in obese children.

Body image: a survey of children in Caribbean Bonaire.

BACKGROUND: In Bonaire, the prevalence of overweight and obesity is twice as high compared with Northern Europe but similar to other Caribbean Islands and the USA. Having a realistic body image may be an important tool in the battle against childhood obesity. Previous studies have demonstrated associations between having a realistic body image and efforts to control weight. The aim of the study was to explore the body image of children in Bonaire. METHODS: In a cross-sectional study from March to May 2015 in Bonaire, weight and height were measured in all children aged 10-14 years attending school. Body mass index (kg/m2) was classified according to the International Obesity Task Force. The children were asked about their body image using a validated questionnaire. RESULTS: Body mass index was measured in 939 of 1029 (91.3%) children aged 10-14 years (51.5% boys) in Bonaire. Of all children, 9.7% was underweight, 57.6% was normal weight, 32.7% was overweight (including obesity) and 11.6% was obese. The question pertaining to body image was completed by 750 of 939 (79.9%) children. Having a realistic perception of body image varied per weight category from 65% in underweight girls to 13% in obese boys. The percentage of obese children who underestimate their weight is high (boys 87%, girls 77%). CONCLUSIONS: In many children in Caribbean Bonaire, perceived body image is not in agreement with actual weight status. This applies especially to obese children. Disagreement between perceived body image and actual weight status may prevent weight management in overweight children. Future research is needed to elucidate determinants of disagreement between body image and actual weight status.

Effectiveness of intervention strategies exclusively targeting reductions in children's sedentary time: a systematic review of the literature.

An increasing number of interventions targeting sedentary behaviour in children have emerged in recent years. Recently published reviews included sedentary behaviour and physical activity interventions. This review critically summarizes evidence on the effectiveness of intervention strategies that exclusively targeted reducing sedentary time in children and adolescents. We performed a systematic literature search in Pubmed, Embase and the Cochrane Library through November 2015. Two independent reviewers selected eligible studies, extracted relevant data and rated the methodological quality using the assessment tool for quantitative studies. We included 21 intervention studies, of which 8 studies scored moderate on methodological quality and 13 studies scored weak. Four out of eight moderate quality studies reported significant beneficial intervention effects.Although descriptions of intervention strategies were not always clearly reported, we identified encouragement of a TV turnoff week and implementing standing desks in classrooms as promising strategies. Due to a lack of high quality studies and inconsistent findings, we found no convincing evidence for the effectiveness of existing interventions targeting solely sedentary behaviour. We recommend that future studies apply mediation analyses to explore which strategies are most effective. Furthermore, to increase the effectiveness of interventions, knowledge of children's motives to engage in sedentary behavior is required, as well as their opinion on potentially effective intervention strategies.

Population Pharmacokinetics of Prednisolone in Relation to Clinical Outcome in Children With Nephrotic Syndrome.

BACKGROUND: The relapse frequency in children with nephrotic syndrome (NS) is highly variable despite standardized prednisolone treatment regimens. Existing evidence on the relationship between prednisolone pharmacokinetics (PK) and clinical response in children with NS is scarce and limited. The aim of this study was to develop a pediatric popPK model for prednisolone based on our previous model based on healthy adults using salivary measurements in children with NS and to correlate clinical outcome with between-subject variability in prednisolone exposure. METHODS: The pharmacokinetics of prednisolone in a well-defined, prospective cohort consisting of 104 children with NS while in remission was determined. Pharmacokinetic parameters were analyzed in relation to relapse patterns and side effects. Noninvasive salivary prednisolone measurements were performed using a sparse sampling strategy. A population pharmacokinetic approach was used to derive individual estimates of apparent clearance (CL/F) and apparent volume of distribution (V/F) from the salivary concentration-time curve, followed by calculation of the area under the curve (AUC) of free prednisolone. The individual free serum prednisolone exposure from prednisolone in saliva was derived from the salivary concentration-time curves. Genetic polymorphisms of CYP3A4, CYP3A5, ABCB1, NR1L2, and POR were explored in relation to between-subject variability of CL/F. RESULTS: Moderate interindividual variability was found for CL/F (CV, 44.7%). Unexplained random between-subject variability (eta) of CL/F was lower in patients carrying 1 or 2 ABCB1 3435C>T alleles compared to wild type: median -0.04 (interquartile range, -0.17 to 0.21) and 0.00 (-0.11 to 0.16) versus 0.17 (-0.08 to 0.47), P = 0.046. Exposure to free prednisolone was not associated with frequent relapses or adverse effects. CONCLUSIONS: This study provides evidence for the possibility of prednisolone drug monitoring through salivary measurements and this may be of particular usefulness in pediatric patients. However, the observed variability in prednisolone exposure, in the therapeutic dose range studied, is not considered to be a major determinant of clinical outcome in children with NS.

Is the prevalence of hypertension in overweight children overestimated?

OBJECTIVES: The aim of this study is to explore different methods for screening and diagnosing hypertension-which definitions and criteria to use-in children and in addition to determine the prevalence of hypertension in Dutch overweight children. DESIGN: A cross-sectional study performed in the Dutch Child Health Care setting. SETTING: Four Child Health Care centres in different cities in the Netherlands. PARTICIPANTS: 969 overweight (including obese) and 438 non-overweight children, median age 11.7 years (range 4.1-17.10), 49% boys. MAIN OUTCOME MEASURES: The main outcome was blood pressure, and the difference in prevalence of hypertension using different criteria for blood pressure interpretation: using the first blood pressure measurement, the mean of two measurements and the lowest of three measurements on two different occasions. RESULTS: Looking at the first measurement alone, 33% of overweight and 21% of non-overweight children had hypertension. By comparing the mean of the first two measurements with reference values, 28% of overweight children and 16% of non-overweight children had hypertension. Based on the lowest of three consecutive measurements, the prevalence decreased to 12% among overweight children and 5% among non-overweight children at visit one and at visit two 4% of overweight children still had hypertension. CONCLUSIONS: The prevalence of hypertension is highly dependent on the definitions and criteria used. We found a prevalence of 4% in overweight children, which is considerably lower than suggested by recent literature (4%-33%). This discrepancy can be explained by our more strict definition of hypertension. However, to draw any conclusions on the prevalence, normal values using the same definition of hypertension should be established. Despite the low prevalence, we recommend measuring blood pressure in all overweight children in view of later cardiovascular morbidity and mortality.

Exclusively breastfed overweight infants are at the same risk of childhood overweight as formula fed overweight infants.

BACKGROUND AND OBJECTIVE: Several early life determinants play a role in childhood obesity. Rapid weight gain and overweight in infancy increases the risk while breast feeding seems to protect against childhood overweight. However, should we worry about exclusively breastfed overweight infants? The aim of the study is to examine the association of feeding type (exclusive breast feeding (EBF), formula feeding or mixed feeding) and overweight at the age of 6 months with the risk of overweight at the age of 5-6 years. METHODS: The Amsterdam Born Children and their Development study is a large prospective population-based birth cohort study conducted in Amsterdam, the Netherlands. Children with complete information pertaining to feeding type and weight status at the age of 6 months and 5-6 years were included (N=3367). EBF was defined as receiving only breast feeding for at least 3 months. Overweight at the ages of 6 months and 5-6 years were defined by the WHO child growth standards and the International Obesity Task Force guidelines, respectively. The association of feeding type and overweight at 6 months with overweight at 5-6 years was assessed using logistic regression analyses. RESULTS: Overweight infants have a 4.10-fold (95% CI 2.91 to 5.78) higher odds of childhood overweight compared with those who were not overweight, independent of feeding type. EBF did not affect the association between infant overweight and childhood overweight. CONCLUSIONS: Overweight in infancy increases the odds of childhood overweight, equally for exclusively breastfed and formula fed infants. Overweight prevention should start before or at birth and applies to formula fed children as well as exclusively breastfed children.

Genetic and in vivo determinants of glucocorticoid sensitivity in relation to clinical outcome of childhood nephrotic syndrome.

Following initial glucocorticoid treatment, the clinical course in children with nephrotic syndrome is highly variable. Intrinsic sensitivity to glucocorticoids might be a determinant of this variability. Functional polymorphisms of the glucocorticoid receptor gene NR3C1 have been associated with either relatively impaired (GR-9ß) or increased (BclI) glucocorticoid sensitivity. Here, in a prospective, well-defined cohort of children with nephrotic syndrome, we evaluated both carriage of GR-9ß+TthIII-1 and BclI haplotypes in 113 children and a dexamethasone suppression test in 90 children in relation to their clinical outcome over a median follow-up of 4.4 years. Carriers of GR-9ß+TthIII-1 had a significantly higher incidence of steroid dependence 13/25 (52%) compared with noncarriers 19/75 (25%) with a hazard ratio adjusted for gender, age, and descent of 3.04 with 95% confidence interval 1.37-6.74. Both first and frequent relapses happened significantly more often in GR-9ß+TthIII-1 carriers than in noncarriers. There were no significant differences in therapeutic outcomes between carriers and noncarriers of the BclI haplotype. Results of the dexamethasone test showed no associations with clinical outcome. Thus, the GR-9ß+TthIII-1 haplotype of the glucocorticoid receptor gene offers new insights into the clinical course of children with nephrotic syndrome.

Monitoring prednisolone and prednisone in saliva: a population pharmacokinetic approach in healthy volunteers.

BACKGROUND: Prednisolone (PLN) is a widely used corticosteroid in a variety of immune-mediated diseases. Treatment regimes generally consist of empirically derived treatment doses, whereas therapeutic response among patients is highly variable. Drug monitoring of serum PLN levels might support a more rational approach to dose selection, yet is invasive and laborious. In analogy to cortisol, salivary PLN may offer a good alternative for serum PLN, being a representative approximation of free serum PLN. The aims of this study were to evaluate the correlation between free serum and salivary PLN levels and to quantify this relationship within a population pharmacokinetic model. METHODS: PLN and prednisone (PN) concentrations were measured in 396 samples from 19 healthy volunteers after oral ingestion of 80 mg PLN. Measurements in serum, ultrafiltrate, and saliva were performed with a recently validated liquid chromatography tandem mass spectrometry method. Population pharmacokinetic analysis was performed with nonlinear mixed effect modeling using NONMEM. RESULTS: Salivary PLN levels correlated well with free serum PLN levels (r = 0.931, P < 0.01). A weaker correlation was found for PN (r = 0.318, P < 0.01), which may be explained by the finding that salivary PN levels mainly seemed to consist of PLN enzymatically converted to PN. Total and free serum PLN concentrations decreased over time after drug administration and showed a nonlinear mutual relationship, consistent with concentration-dependent protein binding. Modeled PLN pharmacokinetics corresponded with previous reports. Low to moderate interindividual variability was found for V/F and CL/F (coefficients of variation were 13.8% and 14.6%, respectively). Free and salivary PLN showed a nonlinear relationship with total PLN. An equation predicting free serum levels from salivary levels was successfully derived from the data. CONCLUSIONS: This study is the first to describe the relationship between salivary and (free) serum PLN using a population pharmacokinetic model. Salivary PLN was found to be a reliable predictor of free and total serum PLN in healthy volunteers. The results of this study encourage further exploration of the use of saliva as a noninvasive and feasible method for drug monitoring of PLN.

[Guideline 'Overweight' for child health care]. / Richtlijn 'Overgewicht' voor de jeugdgezondheidszorg.

The '5th National Growth Study' indicates that the percentage of overweight children in the Netherlands has risen from 9-12% in 1997 to 13-15% in 2009. Child Health Care is a unique setting for promotion of development, growth and behaviour of children, in which tailored prevention can be offered. Detection of overweight in children and intervention by Child Health Care takes place in a multidisciplinary setting linking general practitioners, paediatricians, dieticians, teachers, physiotherapists, pedagogues and psychologists. For overweight children, a change plan is created based on exercise, playing outside, having breakfast every day, as little as possible sweetened beverages and fast-food, and less time spent in front of the television or computer, with fewer energy-rich snacks. As recommended in the Dutch CBO guideline 'Obesity', obese children are referred to a general practitioner or paediatrician.

Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome.

Prolonged prednisolone treatment for the initial episode of childhood nephrotic syndrome may reduce relapse rate, but whether this results from the increased duration of treatment or a higher cumulative dose remains unclear. We conducted a randomized, double-blind, placebo-controlled trial in 69 hospitals in The Netherlands. We randomly assigned 150 children (9 months to 17 years) presenting with nephrotic syndrome to either 3 months of prednisolone followed by 3 months of placebo (n=74) or 6 months of prednisolone (n=76), and median follow-up was 47 months. Both groups received equal cumulative doses of prednisolone (approximately 3360 mg/m(2)). Among the 126 children who started trial medication, relapses occurred in 48 (77%) of 62 patients who received 3 months of prednisolone and 51 (80%) of 64 patients who received 6 months of prednisolone. Frequent relapses, according to international criteria, occurred with similar frequency between groups as well (45% versus 50%). In addition, there were no statistically significant differences between groups with respect to the eventual initiation of prednisolone maintenance and/or other immunosuppressive therapy (50% versus 59%), steroid dependence, or adverse effects. In conclusion, in this trial, extending initial prednisolone treatment from 3 to 6 months without increasing cumulative dose did not benefit clinical outcome in children with nephrotic syndrome. Previous findings indicating that prolonged treatment regimens reduce relapses most likely resulted from increased cumulative dose rather than the treatment duration.

High prevalence of hypertension in obese children in the Caribbean.

BACKGROUND: The prevalence of obesity is increasing worldwide. Obesity in children and adults leads to diabetes mellitus type 2 and cardiovascular disease. AIM: To determine the prevalence of high blood pressure in overweight and obese children in the Caribbean. METHODS: In a cross-sectional study, weight and height were measured in all 5-16-year-old children attending public school in 2008 on Bonaire, an island in the Caribbean. Cut-off values for body mass index (BMI) are defined by the International Obesity Task Force. Blood pressure was measured in all overweight and obese children as well as in a control group with normal weight and compared with reference values from the National High Blood Pressure Working Group on Children. RESULTS: 94% (2023/2152) of all children participated in the study. 17% (335/2023) of the children were overweight (excluding obesity) and a further 12% (246/2023) were obese. Hypertension was found in 13% (67/526) of children of normal weight, in 23% (71/307) of overweight children and in 53% (127/242) of obese children. Compared with normal-weight children, the odds for hypertension were 2.1 (95% CI 1.4-3.0) for overweight children and 7.2 (95% CI 5.0-10.3) for obese children. CONCLUSION: There is a high prevalence of hypertension in overweight and obese children on Bonaire. As hypertension is a harbinger of cardiovascular disease, early detection and treatment of overweight and obese children is of paramount importance and their blood pressure needs to be measured regularly.

High cardiovascular risk in severely obese young children and adolescents.

OBJECTIVE: To assess the prevalence of cardiovascular risk factors in severely obese children and adolescents. METHODS: A nationwide prospective surveillance study was carried out from July 2005 to July 2007 where paediatricians were asked to report all new cases of severe obesity in 2-18-year-old children to the Dutch Paediatric Surveillance Unit. Severe obesity is defined by gender and age-dependent cut-off points for body mass index based on Dutch National Growth Studies corresponding to the adult cut-off point of 35 kg/m(2). Paediatricians were asked to complete a questionnaire for every severely obese child regarding socio-demographic characteristics and cardiovascular risk factors (blood pressure, fasting blood glucose and lipids). RESULTS: In 2005, 2006 and 2007, 94%, 87% and 87%, respectively, of paediatricians in the Netherlands responded to the monthly request from the Dutch Paediatric Surveillance Unit and 500 children with newly diagnosed severe obesity were reported. 72.6% (n=363) of paediatricians responded to a subsequent questionnaire. Cardiovascular risk factor data were available in 255/307 (83%) children who were correctly classified as severely obese. 67% had at least one cardiovascular risk factor (56% hypertension, 14% high blood glucose, 0.7% type 2 diabetes and up to 54% low HDL-cholesterol). Remarkably, 62% of severely obese children aged ≤12 years already had one or more cardiovascular risk factors. CONCLUSION: A high number (2/3) of severely obese children have cardiovascular risk factors. Internationally accepted criteria for defining severe obesity and guidelines for early detection and treatment of severe obesity and comorbidity are urgently needed.

Nephrocalcinosis in preterm neonates.

The prevalence of nephrocalcinosis (NC) in preterm neonates in recent reports is 7-41%. The wide range in prevalence is a consequence of different study populations and ultrasound equipment and criteria, in addition to a moderate interobserver variation. NC in preterm neonates has a multifactorial aetiology, consisting of low gestational age and birth weight, often in combination with severe respiratory disease, and occurs as a result of an imbalance between stone-promoting and stone-inhibiting factors. A limited number of histological studies suggest that calcium oxalate crystals play an important role in NC in premature neonates. In 85% of children resolution of NC occurs in the first years of life. Prematurity, per se, is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. In addition, NC in preterm neonates can have long-term sequelae for glomerular and tubular function. Long-term follow-up of blood pressure and renal function of prematurely born children, especially with neonatal NC, is recommended. Prevention of NC with (low) oral doses of citrate has not resulted in a significant decrease in the prevalence of NC; a higher citrate dosage deserves further study. Future research pertaining to prevention of NC in preterm neonates is crucial.

Regulatory allospecific T cell clones abrogate chronic allograft rejection.

True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig-treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4+CD25+Foxp3+ cells and strong mononuclear cell staining for IL-10 but negligible IFN-gamma, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.