Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.

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This study investigated differences in health-related fitness (20-m shuttle run, handgrip, bent arm hang, standing long jump, shuttle run 4 x 10 m and sit and reach tests) in 2474 Spanish adolescents (1196 boys and 1278 girls; age 13-18.5 years) classed as underweight, normal weight, overweight or obese according to body mass index. Body fat and fat-free mass were derived from skinfold thickness. The prevalence of underweight was higher than obesity in girls (4.8% vs 3.0%, respectively; P<0.05) and the opposite in boys (3.9% vs 5.8%, respectively; P<0.05). Underweight was associated with a higher performance in the bent arm hang test in girls (P<0.05) and a lower performance in handgrip in both genders (P<0.01) compared with normal weight. Overweight and obese adolescents presented a lower performance in 20-m shuttle run, bent arm hang, standing long jump and shuttle run 4 x 10 m tests (P<0.001), but a higher performance in handgrip strength (P<0.001) compared with normal weight. In weight-bearing tests, the association became non-significant after adjusting for fat mass. In conclusion, not only overweight and obesity but also underweight seem to be determinants of health-related fitness in adolescents. The associations could be related to differences in body composition.

Objective: To compare the most commonly used equations to predict body fatness from skinfold thickness, in male and female adolescents, with dual-energy X-ray absorptiometry (DXA) as a reference method of fatness measurement. Design: Cross-sectional nutrition survey. Setting: General adolescent population from Zaragoza (Spain). Subjects and methods: A total of 238 Caucasian adolescents (167 females and 113 males), aged 13.0-17.9 y, were recruited from 15 school groups in 11 public and private schools. The percentage fat mass (%FM) was calculated by using skinfoldthickness equations. Predicted %FM was compared with the reference %FM values, measured by DXA. The lack of agreement between methods was assessed by calculating the bias and its 95% limits of agreement.Results: Most equations did not demonstrate good agreement compared with DXA. However, in male adolescents, Slaughter et al equations showed relative biases that were not dependent on body fatness and the limits of agreement were narrower than those obtained from the rest of equations. In females, Brook's equation showed nonsignificant differences against DXA and the narrowest 95% limits of agreement. Only biases from Brook and Slaughter et al equations were not dependent on body fatness in female adolescents. Conclusions: Accuracy of most of the skinfold-thickness equations for assessment of %FM in adolescents was poor at the individual level. Nevertheless, to predict %FM when a relative index of fatness is required in field or clinical studies, Slaughter et al equations may be used in adolescents from both sexes and the Brook equation in female adolescents. Sponsorship: Instituto de Salud Carlos III, Spain.

Profiling miRNA levels in cells with miRNA microarrays is becoming a widely used technique. Although normalization methods for mRNA gene expression arrays are well established, miRNA array normalization has so far not been investigated in detail. In this study we investigate the impact of normalization on data generated with the Agilent miRNA array platform. We have developed a method to select nonchanging miRNAs (invariants) and use them to compute linear regression normalization coefficients or variance stabilizing normalization (VSN) parameters. We compared the invariants normalization to normalization by scaling, quantile, and VSN with default parameters as well as to no normalization using samples with strong differential expression of miRNAs (heart-brain comparison) and samples where only a few miRNAs are affected (by p53 overexpression in squamous carcinoma cells versus control). All normalization methods performed better than no normalization. Normalization procedures based on the set of invariants and quantile were the most robust over all experimental conditions tested. Our method of invariant selection and normalization is not limited to Agilent miRNA arrays and can be applied to other data sets including those from one color miRNA microarray platforms, focused gene expression arrays, and gene expression analysis using quantitative PCR.