W Ahrens

Anatomical, Histologic, and Genetic Characteristics of Congenital Chest Wall Deformities

There is a large and diverse group of congenital abnormalities of the thorax that manifest as deformities and/or defects of the anterior chest wall and, depending on the severity and concomitant anomalies, may have cardiopulmonary implications. Pectus excavatum, the most common anterior chest deformity, is characterized by sternal depression with corresponding leftward displacement and rotation of the heart. Pectus carinatum, the second most common, exhibits a variety of chest wall protrusions and very diverse clinical manifestations. The cause of these conditions is thought to be abnormal elongation of the costal cartilages. Collagen, as a major structural component of rib cartilage, is implicated by genetic and histologic analysis. Poland syndrome is a unique unilateral chest/hand deficiency that may include rib defects, pectoral muscle deficit, and syndactyly. Cleft sternum is a rare congenital defect resulting from nonfusion of the sternal halves, which leaves the heart unprotected and requires early surgical intervention.

Metabolic syndrome in young children: definitions and results of the IDEFICS study

Objective:To estimate the prevalence of the metabolic syndrome (MetS) using reference standards obtained in European children and to develop a quantitative MetS score and describe its distribution in children.Design and methods:Population-based survey in eight European countries, including 18745 children 2.0 to 10.9 years, recruited during a second survey. Anthropometry (weight, height and waist circumference), blood pressure and serum-fasting triglycerides, HDL cholesterol, glucose and insulin were measured. We applied three widely accepted definitions of the pediatric MetS and we suggest a new definition, to guide pediatricians in decisions about close monitoring or even intervention (values of at least three of the MetS components exceeding the 90th or 95th percentile, respectively). We used a z-score standardisation to calculate a continuous score combining the MetS components.Results:Among the various definitions of MetS, the highest prevalence (5.5%) was obtained with our new definition requiring close observation (monitoring level). Our more conservative definition, requiring pediatric intervention gives a prevalence of 1.8%. In general, prevalences were higher in girls than in boys. The prevalence of metabolic syndrome is highest among obese children. All definitions classify a small percentage of thin or normal weight children as being affected. The metabolic syndrome score shows a positive trend with age, particularly regarding the upper percentiles of the score.Conclusions:According to different definitions of pediatric MetS, a non-negligible proportion of mostly prepubertal children are classified as affected. We propose a new definition of MetS that should improve clinical guidance. The continuous score developed may also serve as a useful tool in pediatric obesity research. It has to be noted, however, that the proposed cutoffs are based on a statistical definition that does not yet allow to quantify the risk of subsequent disease.

Percentile reference values for anthropometric body composition indices in European children from the IDEFICS study

Introduction:To characterise the nutritional status in children with obesity or wasting conditions, European anthropometric reference values for body composition measures beyond the body mass index (BMI) are needed. Differentiated assessment of body composition in children has long been hampered by the lack of appropriate references.Objectives:The aim of our study is to provide percentiles for body composition indices in normal weight European children, based on the IDEFICS cohort (Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and infantS).Methods:Overall 18 745 2.0–10.9-year-old children from eight countries participated in the study. Children classified as overweight/obese or underweight according to IOTF (N=5915) were excluded from the analysis. Anthropometric measurements (BMI (N=12 830); triceps, subscapular, fat mass and fat mass index (N=11 845–11 901); biceps, suprailiac skinfolds, sum of skinfolds calculated from skinfold thicknesses (N=8129–8205), neck circumference (N=12 241); waist circumference and waist-to-height ratio (N=12 381)) were analysed stratified by sex and smoothed 1st, 3rd, 10th, 25th, 50th, 75th, 90th, 97th and 99th percentile curves were calculated using GAMLSS.Results:Percentile values of the most important anthropometric measures related to the degree of adiposity are depicted for European girls and boys. Age- and sex-specific differences were investigated for all measures. As an example, the 50th and 99th percentile values of waist circumference ranged from 50.7–59.2 cm and from 51.3–58.7 cm in 4.5– to <5.0-year-old girls and boys, respectively, to 60.6–74.5 cm in girls and to 59.9–76.7 cm in boys at the age of 10.5–10.9 years.Conclusion:The presented percentile curves may aid a differentiated assessment of total and abdominal adiposity in European children.

Gestational weight gain and adiposity, fat distribution, metabolic profile, and blood pressure in offspring: the IDEFICS project.

Objective:To investigate the association between gestational weight gain (GWG) and total adiposity, body fat distribution, blood pressure (BP), and metabolic profile in offspring.Design:Cross-sectional study.Methods:Body mass index (BMI), waist, subscapular and tricipital skinfolds, and BP were measured and blood samples drawn in 12 775 children (aged 2–9 years) from the IDEFICS cohort. Overweight/obesity was defined by IOTF criteria. Parents filled in a questionnaire investigating child and familiar medical history and lifestyle. A section was dedicated to pregnancy history (including GWG).Results:Anthropometric indices linearly and significantly increased across GWG tertiles (BMI z-score: tertile I =0.08, 0.03–0.13; tertile II =0.16, 0.12–0.21; tertile III =0.34, 0.28–0.40, P<0.01, mean, 95% CI) by analysis of covariance (ANCOVA) adjusted by child sex, age and practice of sport, birth weight, current maternal BMI, parental education, gestational age, age at delivery, alcohol and smoking during pregnancy, maternal diabetes mellitus, gestational hypertension, and breastfeeding duration. After inclusion of BMI z-score among covariates, HbA1c significantly increased across tertiles (P=0.009) while no differences were observed for BP, serum insulin, HOMA index, blood glucose and lipids. The adjusted risk of overweight/obesity significantly increased by 14 and 22% in tertiles II and III respectively, in comparison with tertile I by logistic regression analysis controlling for covariates.Conclusion:Maternal GWG is an independent predictor of total adiposity and body fat distribution in offspring during infancy. Exposure to perinatal factors should be taken into account for early prevention of overweight and obesity.

Percentiles of fasting serum insulin, glucose, HbA1c and HOMA-IR in pre-pubertal normal weight European children from the IDEFICS cohort

Objectives:The aim of this study is to present age- and sex-specific reference values of insulin, glucose, glycosylated haemoglobin (HbA1c) and the homeostasis model assessment to quantify insulin resistance (HOMA-IR) for pre-pubertal children.Methods:The reference population consists of 7074 normal weight 3- to 10.9-year-old pre-pubertal children from eight European countries who participated in at least one wave of the IDEFICS (‘identification and prevention of dietary- and lifestyle-induced health effects in children and infants’) surveys (2007–2010) and for whom standardised laboratory measurements were obtained. Percentile curves of insulin (measured by an electrochemiluminescence immunoassay), glucose, HbA1c and HOMA-IR were calculated as a function of age stratified by sex using the general additive model for location scale and shape (GAMLSS) method.Results:Levels of insulin, fasting glucose and HOMA-IR continuously show an increasing trend with age, whereas HbA1c shows an upward trend only beyond the age of 8 years. Insulin and HOMA-IR values are higher in girls of all age groups, whereas glucose values are slightly higher in boys. Median serum levels of insulin range from 17.4 and 13.2 pmol l−1 in 3–<3.5-year-old girls and boys, respectively, to 53.5 and 43.0 pmol l−1 in 10.5–<11-year-old girls and boys. Median values of glucose are 4.3 and 4.5 mmol l−1 in the youngest age group and 49.3 and 50.6 mmol l−1 in the oldest girls and boys. For HOMA-IR, median values range from 0.5 and 0.4 in 3–<3.5-year-old girls and boys to 1.7 and 1.4 in 10.5–<11-year-old girls and boys, respectively.Conclusions:Our study provides the first standardised reference values for an international European children’s population and provides the, up to now, largest data set of healthy pre-pubertal children to model reference percentiles for markers of insulin resistance. Our cohort shows higher values of Hb1Ac as compared with a single Swedish study while our percentiles for the other glucose metabolic markers are in good accordance with previous studies.

The use of a novel MUC1 antibody to identify cancer stem cells and circulating MUC1 in mice and patients with pancreatic cancer.

MUC1 is over‐expressed and aberrantly glycosylated in >60% of human pancreatic cancer (PC). Development of novel approaches for detection and/or targeting of MUC1 are critically needed and should be able to detect MUC1 on PC cells (including cancer stem cells) and in serum.

Reference values of whole-blood fatty acids by age and sex from European children aged 3-8 years

Objectives:To establish reference values for fatty acids (FA) especially for n-3 and n-6 long-chain polyunsaturated FAs (LC PUFA) in whole-blood samples from apparently healthy 3–8-year-old European children. The whole-blood FA composition was analysed and the age- and sex-specific distribution of FA was determined.Design and subjects:Blood samples for FA analysis were taken from 2661 children of the IDEFICS (identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study cohort. Children with obesity (n=454) and other diseases that are known to alter the FA composition (n=450) were excluded leaving 1653 participants in the reference population.Measurements:The FA composition of whole blood was analysed from blood drops by a rapid, validated gas chromatographic method.Results:Pearson correlation coefficients showed an age-dependent increase of C18:2n-6 and a decrease of C18:1n-9 in a subsample of normal weight boys and girls. Other significant correlations with age were weak and only seen either in boys or in girls, whereas most of the FA did not show any age dependence. For age-dependent n-3 and n-6 PUFA as well as for other FA that are correlated with age (16:0, C18:0 and C18:1n-9) percentiles analysed with the general additive model for location scale and shape are presented. A higher median in boys than in girls was observed for C20:3n-6, C20:4n-6 and C22:4n-6.Conclusions:Given the reported associations between FA status and health-related outcome, the provision of FA reference ranges may be useful for the interpretation of the FA status of children in epidemiological and clinical studies.

Reference values of bone stiffness index and C-terminal telopeptide in healthy European children

Background/Objective:Quantitative ultrasound measurements and bone metabolic markers can help to monitor bone health and to detect impaired skeletal development. Population-based reference values for children may serve as a basis for preventive measures to reduce the risk of osteoporosis and osteoporotic fractures in later life. This is the first paper providing age-, sex- and height-specific reference values for bone stiffness index (SI) and serum carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in healthy, apparently prepubertal children.Subjects/Methods:In the population-based IDEFICS baseline survey (2007–2008) and follow-up (2009–2010), 18 745 children from eight European countries were newly recruited. A total of 10 791 2–10.9-year-old and 1646 3–8.9-year-old healthy children provided data on SI of the right and left calcaneus and serum CTX, respectively. Furthermore, height and weight were measured. Percentile curves were calculated using the General Additive Model for Location Scale and Shape (GAMLSS) to model the distribution of SI and CTX depending on multiple covariates while accounting for dispersion, skewness, and the kurtosis of this distribution.Results:SI was negatively associated with age and height in children aged 2–5 years, whereas a positive association was observed in children aged 6–10 years. The dip in SI occurred at older age for higher SI percentiles and was observed earlier in taller children than in smaller children. The CTX reference curves showed a linear-positive association with age and height. No major sex differences were observed for the SI and CTX reference values.Conclusion:These reference data lay the ground to evaluate bone growth and metabolism in prepubertal children in epidemiological and clinical settings. They may also inform clinical practice to monitor skeletal development and to assess adverse drug reactions during medical treatments.

Invasive biliary mucinous cystic neoplasm: a review

OBJECTIVES Biliary mucinous cystic neoplasms (BMCNs) are recently redefined rare liver tumours in which insufficient recognition frequently leads to an incorrect initial or delayed diagnosis. A concise review of the subtle, sometimes non-specific, clinical, serologic and radiographic features will allow for a heightened awareness and more comprehensive understanding of these entities. METHODS Literature relating to the presentation, diagnosis, treatment, pathology and outcomes of BMCNs and published prior to March 2012 was reviewed. RESULTS Biliary mucinous cystic neoplasms most commonly occur in females (≥60%) in the fifth decade of life. Clinical symptoms, serologic markers and imaging modalities are unreliable for diagnosis of BMCNs, which leads to misdiagnosis in 55-100% of patients. Perioperative cyst aspiration is not recommended as invasive BMCNs can only be differentiated from non-invasive BMCNs by microscopic evaluation for the presence of ovarian-type stroma. Intraoperative biopsy and frozen section(s) are essential to differentiate BMCNs from other cystic liver lesions. The treatment of choice is complete excision and can result in excellent survival with initial correct diagnosis. CONCLUSIONS A low threshold for considering BMCN in the differential diagnosis of cystic liver lesions and increased attentiveness to its subtle diagnostic characteristics are imperative. The complete surgical resection of BMCNs and the use of appropriate nomenclature are necessary to improve outcomes and accurately define prognosis.

A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis

We report that Mucin1 (MUC1), a transmembrane glycoprotein that is overexpressed in >80% of pancreatic ductal adenocarcinoma (PDA), induced a pro-angiogenic tumor microenvironment by increasing the levels of neuropilin-1 (NRP1, a co-receptor of vascular endothelial growth factor (VEGF)) and its ligand VEGF. Expression of tumor-associated MUC1 (tMUC1) positively correlated with NRP1 levels in human and mouse PDA. Further, tMUC1hi PDA cells secreted high levels of VEGF and expressed high levels of VEGF receptor 2 (VEGFR2) and its phosphorylated forms as compared with tMUC1low/null PDA. This enabled the tMUC1hi/NRP1hi PDA cells to (a) induce endothelial cell tube formation, (b) generate long ectopic blood vessels and (c) enhance distant metastasis in a zebrafish xenograft model. Concurrently, the proteins associated with epithelial-to-mesenchymal transition, N-cadherin and Vimentin, were highly induced in these tMUC1/NRP1hi PDA cells. Hence, blocking signaling via the NRP1–VEGF axis significantly reduced tube formation, new vessel generation and metastasis induced by tMUC1hi PDA cells. Finally, we show that blocking the interaction between VEGF165 and NRP1 with a NRP1 antagonist significantly reduced VEGFR signaling and PDA tumor growth in vivo. Taken together, our data suggest a novel molecular mechanism by which tMUC1 may modulate NRP1-dependent VEGFR signaling in PDA cells.