Aims/hypothesis In adults, circulating inflammatory mediators and activated CD14 ++ monocytes link obesity to its metabolic and cardiovascular complications. However, it is largely unknown whether these inflammatory changes already occur in childhood obesity. To survey inflammatory changes during the early stages of obesity, we performed a comprehensive analysis of circulating inflammatory mediators, monocyte populations and their function in childhood obesity. Methods In lean and obese children aged 6 to 16 years (n0 96), 35 circulating inflammatory mediators including adipokines were measured. Hierarchical cluster analysis of the inflammatory mediator profiles was performed to investigate associations between inflammatory mediator clusters and clinical variables. Whole-blood monocyte phenotyping and functional testing with the toll-like receptor 4 ligand, lipopolysaccharide, were also executed. Results First, next to leptin, the circulating mediators chemerin, tissue inhibitor of metalloproteinase 1, EGF and TNF receptor 2 were identified as novel inflammatory mediators that are increased in childhood obesity. Second, cluster analysis of the circulating mediators distinguished two obesity clusters, two leanness clusters and one mixed cluster. All clusters showed distinct inflammatory mediator profiles, together with differences in insulin sensitivity and other clinical variables. Third, childhood obesity was associated with increased CD14 ++ monocyte numbers and an activated phenotype of the CD14 ++ monocyte subsets. Conclusions/interpretation Inflammatory mediator clusters were associated with insulin resistance in obese and lean ++ monocyte subsets, which is associated with increased development of atherosclerosis in obese adults, was also readily detected in obese children. Our results indicate that inflammatory mechanisms linking obesity to its metabolic and cardiovascular complications are already activated in childhood obesity.

ABSTRACT:The vitamin K-dependent protein osteocalcin is thought to play an important role in bone metabolism. Osteocalcin contains glutamic acid (Gla) residues, which have a high affinity for calcium. Vitamin K acts as an indispensable cofactor for the formation of these residues. Inadequate dietary vitamin K intake results in the synthesis of undercarboxylated (i.e. inactive) osteocalcin (ucOC). In adults, low vitamin K status of bone is associated with low bone density and increased risk of osteoporotic fractures. Little is known about vitamin K status and bone health in children. We used a cross-sectional study design to compare the vitamin K status of bone in healthy children (n ϭ 86) with that of adults (n ϭ 30). In children, a marked elevation of the ratio of ucOC/carboxylated osteocalcin (cOC), indicative of a poor vitamin K status, was observed. This difference persisted after adjusting for age, gender, puberty, height, weight. Furthermore, a marked correlation between the bone markers for bone metabolism and ucOC and cOC was found in the children's group. These findings suggest a pronounced low vitamin K status of bone during growth. The question remains, however, whether children would benefit from higher vitamin K intake, for instance, by improved bone health or stronger bones. V itamin K and vitamin K-dependent proteins (also known as Gla proteins) are best known for their role in blood coagulation. However, Gla proteins are also involved in other physiologic processes (e.g. bone metabolism) (1,2). Osteocalcin is a bone Gla protein and synthesized by osteoblasts (3). It constitutes approximately 20% of the noncollagenous protein found in human bone (4).Vitamin K acts as a cofactor in the posttranslational carboxylation of all Gla proteins. In this process, glutamate residues are converted into ␥-carboxyglutamate (Gla) (5). Gla residues have a high affinity for calcium, and their complex formation with calcium ions was demonstrated to be essential for the function of all Gla proteins currently known.To adequately carboxylate osteocalcin, the osteoblast requires sufficient vitamin K (6). In case of vitamin K deficiency, ucOC will be produced. Bioavailable vitamin K is mainly derived from nutritional sources. The gut flora also produces vitamin K, but at the site of synthesis (colon) its absorption is negligible (7,8). The two most important forms of vitamin K are phylloquinone (vitamin K 1 ) and the group of K 2 vitamins (menaquinones). Dietary sources of phylloquinone are green vegetables (spinach, broccoli) and some plant oils (9). Menaquinones are found in meat and fermented foods like cheese (10). Hence, inadequate intake of vitamin K will lead to the production of undercarboxylated (i.e. inactive) Gla proteins.Methods have been developed to distinguish between cOC and ucOC fractions of osteocalcin (11,12). The ratio between ucOC and cOC (UCR) as well as circulating ucOC levels are used as indicators for the vitamin K status of bone (2,13,14). The UCR is probably the most sensitive marker for bone ...

Parents' preferences for unsolicited findings (UFs) from diagnostic whole-exome sequencing (WES) for their children remain largely unexplored. Our aim was to gain insight into parental considerations favoring acceptance/decline of UFs pertaining to their child. We conducted 20 qualitative, semistructured interviews with parents (n = 34) of children with a developmental delay, aged o1 to 17 years, after consenting to WES, but before feedback of results. Key findings from our study were that all parents favored acceptance of UFs for medically actionable conditions in childhood, but that preferences and considerations diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier-status. Sometimes non-medical utility considerations (considerations of usefulness of knowing UFs, not rooted in (preventive) medical treatment or controls) were given in favor of disclosure of UFs. Sometimes the child's future autonomy formed a reason to withhold UFs at present, despite an unfavorable prognosis concerning the child's cognitive capabilities. Some parents only preferred receiving UFs if these findings were directly related to their reasons for seeking a diagnosis. These findings are essential for developing morally responsible policy and for counseling. Further research should focus on whether considerations of non-medical utility alone can justify disclosure of UFs and whether reasons for seeking a diagnosis place further constraints on what UFs may be returned/withheld. How parents can be aided in contemplating different scenarios regarding their child's future development also deserves further inquiry.

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