Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data

Asfotase alfa is an enzyme replacement therapy approved for treatment of patients with pediatric-onset hypophosphatasia (HPP), a rare, inherited, systemic disease causing impaired skeletal mineralization, short stature, and reduced physical function in children. The role of dual X-ray absorptiometry (DXA) in the assessment of children with HPP has been insufficiently explored. This post hoc analysis included pooled DXA data from 2 open-label, multicenter studies in 19 children with HPP. The study population was aged ≥5 to <18 years and had received asfotase alfa for ≤6.6 years at enrollment (male: 79%; median age at enrollment: 10.4 y [range: 5.9–16.7]; treatment duration: 6.3 y [range: 0.1–6.6]. Baseline height Z-scores indicated short stature (median [min, max]: −1.26 [−6.6, 0]); mean [SD]: −2.30 [1.97]), thus requiring height adjustment of DXA Z-scores. At Baseline, few patients had height-adjusted bone mineral density (BMDht) Z-scores of −2 or less for whole body (n = 3) or lumbar spine (n = 5). In treated patients, mean whole body and lumbar spine BMDht Z-scores did not change over time, but whole body and lumbar spine height- adjusted bone mineral content (BMCht) Z-scores increased significantly from Baseline to Last Assessment (P ≤ 0.0056). Improvements in Radiographic Global Impression of Change (RGI-C) scale scores correlated significantly with increases in whole body and lumbar spine BMCht Z-scores (P < 0.05) but not BMDht Z-Scores. Improvements in Rickets Severity Score (RSS) correlated significantly with increases in lumbar spine BMDht Z-scores and whole body BMCht Z-scores (P < 0.05). No significant correlations were observed between any DXA and bone histomorphometry measure. These findings suggest that DXA BMD Z-scores, which are commonly used in clinical practice, have limited utility in assessing deficient bone mineralization in patients with HPP. Although BMCht Z-scores increased significantly over time with asfotase alfa therapy, the lack of significant changes in more than one DXA parameter suggests that this tool may not be useful in everyday clinical practice. Furthermore, the use of BMC as an independent metric is not typical or recommended by guidelines. Complementary measures, such as skeletal radiographs supplemented with age-appropriate functional assessments, should be considered.This work was supported by Alexion Pharmaceuticals, Inc., Boston, MA, USA

ПРОФІЛАКТИКА ЙОДОДЕФІЦИТНИХ ЗАХВОРЮВАНЬ В ТЕРНОПІЛЬСЬКОМУ РЕГІОНІ

The necessity of shortage iodine prophylaxy in Ukraine was discovered in the article. У статті висвітлюється питання про необхідність профілактики йодного дефіциту в Україні

Conditional probabilities in Ponzano-Regge minisuperspace

We examine the Hartle-Hawking no-boundary initial state for the Ponzano-Regge formulation of gravity in three dimensions. We consider the behavior of conditional probabilities and expectation values for geometrical quantities in this initial state for a simple minisuperspace model consisting of a two-parameter set of anisotropic geometries on a 2-sphere boundary. We find dependence on the cutoff used in the construction of Ponzano-Regge amplitudes for expectation values of edge lengths. However, these expectation values are cutoff independent when computed in certain, but not all, conditional probability distributions. Conditions that yield cutoff independent expectation values are those that constrain the boundary geometry to a finite range of edge lengths. We argue that such conditions have a correspondence to fixing a range of local time, as classically associated with the area of a surface for spatially closed cosmologies. Thus these results may hint at how classical spacetime emerges from quantum amplitudes.Comment: 26 pages including 10 figures, some reorganization in the presentation of results, expanded discussion of results in the context of 2+1 gravity in the Witten variables, 3 new reference

Determinants of Catch-Up Growth in International Adoptees from Eastern Europe

Children raised in orphanages frequently experience growth suppression due to multiple risk factors. Placing such children in more nurturing environments through adoption leads to significant catch-up growth (CUG), the determinants of which are not entirely understood. The goal of this study was to perform an auxological evaluation and examine the degree and correlates of CUG in international adoptees. Children adopted from Eastern Europe, (n = 148, 71 males), 7 to 59 months of age, were recruited within 3 weeks of their arrival to the US. At baseline, mean height SDS was −1.2 ± 1.1 and 22% were <−2 SDS for height. IGF-1 and/or IGFBP-3 levels <−2 SDS were present in 32%. CUG, defined as a gain of >+0.5 in height SDS, was seen in 62% of adoptees at 6 months after adoption; 7% of children remained <−2 SDS for height (two had growth hormone deficiency). Growth factors improved in the majority of children. Younger age, greater degree of initial growth failure, and higher caloric intake were significantly associated with improved linear growth in multiple regression models. In summary, most adoptees demonstrate excellent CUG within six months after adoption. If growth failure persists after 6 months of appropriate caloric intake, nutrition-independent causes should be considered

Quantum Gravity in 2+1 Dimensions: The Case of a Closed Universe

In three spacetime dimensions, general relativity drastically simplifies, becoming a ``topological'' theory with no propagating local degrees of freedom. Nevertheless, many of the difficult conceptual problems of quantizing gravity are still present. In this review, I summarize the rather large body of work that has gone towards quantizing (2+1)-dimensional vacuum gravity in the setting of a spatially closed universe.Comment: 61 pages, draft of review for Living Reviews; comments, criticisms, additions, missing references welcome; v2: minor changes, added reference

Novel Cytochrome P450, cyp6a17, Is Required for Temperature Preference Behavior in Drosophila

Perception of temperature is an important brain function for organisms to survive. Evidence suggests that temperature preference behavior (TPB) in Drosophila melanogaster, one of poikilothermal animals, is regulated by cAMP-dependent protein kinase (PKA) signaling in mushroom bodies of the brain. However, downstream targets for the PKA signaling in this behavior have not been identified. From a genome-wide search for the genes regulated by PKA activity in the mushroom bodies, we identified the cyp6a17 Cytochrome P450 gene as a new target for PKA. Our detailed analysis of mutants by genetic, molecular and behavioral assays shows that cyp6a17 is essential for temperature preference behavior. cyp6a17 expression is enriched in the mushroom bodies of the adult brain. Tissue-specific knockdown and rescue experiments demonstrate that cyp6a17 is required in the mushroom bodies for normal temperature preference behavior. This is the first study, to our knowledge, to show PKA-dependent expression of a cytochrome P450 gene in the mushroom bodies and its role as a key factor for temperature preference behavior. Taken together, this study reveals a new PKA-Cytochrome P450 pathway that regulates the temperature preference behavior

A Cytochrome P450 Conserved in Insects Is Involved in Cuticle Formation

The sequencing of numerous insect genomes has revealed dynamic changes in the number and identity of cytochrome P450 genes in different insects. In the evolutionary sense, the rapid birth and death of many P450 genes is observed, with only a small number of P450 genes showing orthology between insects with sequenced genomes. It is likely that these conserved P450s function in conserved pathways. In this study, we demonstrate the P450 gene, Cyp301a1, present in all insect genomes sequenced to date, affects the formation of the adult cuticle in Drosophila melanogaster. A Cyp301a1 piggyBac insertion mutant and RNAi of Cyp301a1 both show a similar cuticle malformation phenotype, which can be reduced by 20-hydroxyecdysone, suggesting that Cyp301a1 is an important gene involved in the formation of the adult cuticle and may be involved in ecdysone regulation in this tissue

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects

Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH