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Background: Fibroblast growth factor 21 (FGF21) is an essential metabolic regulator that adapts to changes in nutritional status. Severe childhood undernutrition induces elevated FGF21 levels, contributing to growth hormone (GH) resistance and subsequent linear growth attenuation potentially through a direct action on chondrocytes., Methods: In this study, we assessed expression of the components of both GH and FGF21 pathways in rare and unique human growth plates obtained from children. Moreover, we investigated the mechanistic interplay of FGF21 on GH receptor (GHR) signaling in a heterologous system., Results: Chronic FGF21 exposure increased GH-induced GHR turnover and SOCS2 expression, leading to the inhibition of STAT5 phosphorylation and IGF-1 expression. The clinical significance of FGF21 signaling through GH receptors was tested in nutritionally driven growth failure seen in very preterm (VPT) infants right after birth. VPT infants display an immediate linear growth failure after birth followed by growth catch-up. Consistent with the in vitro model data, we show that circulating FGF21 levels were elevated during deflection in linear growth compared to catch-up growth and were inversely correlated with the length velocity and circulating IGF1 levels., Conclusions: This study further supports a central role of FGF21 in GH resistance and linear growth failure and suggests a direct action on the growth plate., Competing Interests: Author FZ is in the editorial board of Frontiers for Endocrinology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mistry, Silvennoinen, Zaman, Sävendahl, Mariniello, Hall, Howard, Dunkel, Sankilampi and Guasti.)

Context: The human adrenal cortex changes with fetal-neonatal transition from the fetal to the adult organ, accompanied by changes in the steroid metabolome., Objective: As it is unclear how the observed developmental changes differ between preterm and full-term neonates, we investigated whether the involution of the fetal adrenals is following a fixed time course related to postmenstrual age or whether it is triggered by birth. Furthermore, the fetal and postnatal androgen metabolome of preterm infants was characterized in comparison to term babies., Methods: This was a prospective, longitudinal, 2-center study collecting spot urines of preterm and term infants during the first 12 to 18 months of life. Steroid metabolites were measured from spot urines by gas chromatography-mass spectrometry. Data relating were modeled according to established pre- and postnatal pathways., Results: Fetal adrenal involution occurs around term-equivalent age in preterm infants and is not triggered by premature birth. Testosterone levels are higher in preterm infants at birth and decline slower until term compared to full-term babies. Dihydrotestosterone levels and the activity of the classic androgen biosynthesis pathway are lower in premature infants as is 5α-reductase activity. No difference was found in the activity of the alternate backdoor pathway for androgen synthesis., Conclusion: Human adrenal involution follows a strict timing that is not affected by premature birth. By contrast, prematurity is associated with an altered androgen metabolome after birth. Whether this reflects altered androgen biosynthesis in utero remains to be investigated., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Carnitine has an essential role in energy metabolism with possible neuroprotective effects. Very preterm (VPT, <32 gestation weeks) infants may be predisposed to carnitine deficiency during hospitalization. We studied the associations of carnitine intake and serum carnitine levels with growth and brain size at term equivalent age (TEA) in VPT infants. This prospective cohort study included 35 VTP infants admitted to Kuopio University Hospital, Finland. Daily nutrient intakes were registered at postnatal weeks (W) 1 and 5, and serum carnitine levels were determined at W1, W5, and TEA. The primary outcomes were weight, length, and head circumference Z-score change from birth to TEA, as well as brain size at TEA in magnetic resonance imaging. Carnitine intake at W1 and W5, obtained from enteral milk, correlated positively with serum carnitine levels. Both carnitine intake and serum levels at W1, W5, and TEA showed a positive correlation with weight, length, and head circumference Z-score change and with brain size at TEA. In linear models, independent positive associations of carnitine intake and serum carnitine levels with length and head circumference Z-score change and brain size at TEA were seen. In VPT infants, sufficient carnitine intake during hospitalization is necessary since it is associated with better postnatal growth and larger brain size at term age.

Background: Scarce data exist on the impact of granulocyte-colony stimulating factor (G-CSF) type on the mobilizing capacity of CD34 + cells, graft cellular composition, and outcome in myeloma (MM) patients., Patients and Methods: In this prospective multicenter study, 70 patients with MM received filgrastim (FIL) and 20 patients received pegfilgrastim (PEG) as a G-CSF after low-dose cyclophosphamide. Flow cytometry was used to analyze the mobilization of CD34 + cells and cellular composition of blood grafts, hematologic recovery, and survival after auto-SCT according to the G-CSF choice., Results: The CD34 + cell yield of the first apheresis was higher in the FIL group (5.3 vs. 4.2 × 10 6 /kg, p = .025). The better mobilizing capacity was observed in the FIL group especially after bortezomib-based induction based on the higher first apheresis yield of CD34 + cells (7.5 vs. 4.4 × 10 6 /kg, p = .001). The median CD19 + cell count (1.0 vs. 0.4 × 10 6 /kg, p = .010) and the number of CD3 + T lymphocytes (43.1 vs. 31.8 × 10 6 /kg, p = .122) in the infused graft were higher in the patients mobilized with FIL. Both early (day +15) (56 vs. 108 × 10 9 /L, p = .002) and later platelet recovery at 6 months (191 vs. 226 × 10 9 /L, p = .026) were faster in the PEG group., Conclusion: G-CSF type seems to impact on the mobilization capacity and cellular composition of infused graft and also platelet recovery post-transplant. A randomized study might be warranted to verify the effects of G-CSF choice in the mobilization field., (© 2021 AABB.)

Context: The hormone fibroblast growth factor 21 (FGF21) is a key metabolic regulator in the adaptation to fasting. In food-restricted mice, inhibition of skeletal growth is mediated by the antagonistic effect of FGF21 on GH action in the liver and growth plate., Objective: The objective of the study was to assess the role of FGF21 in growth regulation in humans using postnatal growth failure of very preterm infants as a model., Design: FGF21 levels were measured serially in very preterm infants, and their linear growth evaluated from birth to term-equivalent age. Primary chondrocytes obtained from pediatric donors were used to test whether FGF21 can directly interfere with GH signaling., Results: A negative association (β -.415, P < .005, linear regression model) of FGF21 levels with the change in SD score for length was found. In primary chondrocytes, FGF21 upregulated basal and GH-induced SOCS2 expression and inhibited GH-induced signal transducer and activator of transcription 5 (STAT5) phosphorylation as well as GH-induced COLII and ALP expression. Finally, FGF21 inhibited GH-induced IGF-1 expression and cell proliferation, indicating GH resistance. However, FGF21 did not affect IGF-1-induced cell proliferation., Conclusions: Elevated FGF21 serum levels during the first weeks of life are independently associated with postnatal growth failure in preterm infants. Furthermore, our data provide mechanistic insights into GH resistance secondary to prematurity and may offer an explanation for the growth failure commonly seen in chronic conditions of childhood.

Giant cell tumors (GCTs) of the bone are rare, usually benign but locally aggressive neoplasms that primarily occur in the epiphyses of long bones. They seldom develop in the cranium; when they do, they involve principally the sphenoid and temporal bones. These tumors usually affect young adults, and few reports in children have been published. Primary malignant GCTs of the skull are even more uncommon. The 3 published cases all involved adults over 40 years of age. Herein, the authors present a case of a highly aggressive primary malignant GCT of the posterior fossa in a 5-week old preterm infant. One month after the gross-total resection of the tumor found in the bone, the infant's condition rapidly deteriorated and she died. Magnetic resonance imaging and postmortem examination revealed a tumor larger than it had been before the operation, with expansion toward the brain. To the best of the authors' knowledge, this is the youngest patient reported with a primary malignant GCT of the skull, and actually the first case in a pediatric patient. In addition, the extremely high growth rate of the tumor in the postoperative period renders this case the most aggressive primary malignant GCT of the cranium described so far.

Objective: A linguistic multi-feature mismatch negativity (MMN) paradigm with five types of changes (vowel, vowel-duration, consonant, frequency (F0), and intensity) in Finnish syllables was used to determine speech-sound discrimination in 17 normally-developing 6-year-old children. The MMNs for vowel and vowel-duration were also recorded in an oddball condition in order to compare the two paradigms. Similar MMNs in the two paradigms would suggest that they tap the same processes. This would promote the usefulness of the more time-efficient multi-feature paradigm for future studies in children., Methods: MMNs to five deviant types were recorded in the multi-feature paradigm in which these deviants (total of 50%) were presented in an alternating fashion with standards (50%). An oddball condition with vowel and vowel-duration deviants served as a control., Results: The linguistic multi-feature paradigm elicited significant MMN responses to all changes used and the responses were comparable to the ones recorded with the traditional oddball paradigm. Compared to a previous adult study (Pakarinen S, Lovio R, Huotilainen M, Alku P, Näätänen R, Kujala T. Fast multi-feature paradigm for recording several mismatch negativities (MMNs) to phonetic and acoustic changes in speech sounds. Biol Psychol, submitted for publication), the MMN amplitudes seemed to be smaller and of longer latencies in general in children than in adults., Conclusions: The new time-efficient paradigm can be used in studies addressing cortical speech-sound discrimination in young children., Significance: The multi-feature paradigm enables fast (20 min) recording of MMNs for five speech-sound features. In future, it might be useful in detecting abnormalities in speech discrimination profiles of children with possible language-related disorders.