The prediction of estimated cerebral perfusion pressure with trans-systolic time in preterm and term infants.

It is important to monitor cerebral perfusion in infants because hypo- and hyperperfusion can contribute to neurological injury. This study aimed to clarify the relationship between trans-systolic time (TST) and critical closing pressure (CrCP) or estimated cerebral perfusion pressure (CPPe) in neonates. Moreover, we aimed to determine the TST values in preterm and term infants with stable cerebral perfusion to clarify normative reference data. This multicentre prospective study included infants with arterial lines admitted to the neonatal intensive care units between December 2021 and August 2023. TST, CrCP, and CPPe were calculated using middle cerebral artery waveforms recorded using transcranial Doppler ultrasonography when clinicians collected arterial blood samples. Three hundred and sixty samples were obtained from 112 infants with a gestational age of 32 (interquartile range, 27-37) weeks and a birth weight of 1481 (956-2355) g. TST was positively correlated with CPPe (r = 0.60, p < 0.001), but not with CrCP (r = 0.08, p = 0.10). The normative reference values of TST in preterm and term infants without samples of hyper- or hypocapnia and/or hyper- or hypotension, which may affect cerebral perfusion, were as follows: ≤ 29 weeks, 0.12 (0.11-0.14) s; 30-36 weeks, 0.14 (0.12-0.15) s; and ≥ 37 weeks, 0.16 (0.14-0.17) s, respectively.  Conclusion: TST in neonates significantly correlated with CPPe, but not with CrCP. TST may be a good predictor of cerebral perfusion and potentially have wider clinical applications. What is Known: • Trans-systolic time (TST) is used in evaluating the effects of increased intracranial pressure on cerebral haemodynamics. However, little is known about the efficacy of TST in predicting neonatal cerebral perfusion pressure. What is New: • This study added evidence that TST correlated with estimated cerebral perfusion pressure, but not with critical closing pressure. Additionally, we showed the normative reference values of the TST in preterm and term infants.

High-fat diet during pregnancy lowers fetal weight and has a long-lasting adverse effect on brown adipose tissue in the offspring.

Maternal obesity and malnutrition during gestation and lactation have been recognized to increase the risk of obesity and metabolic disorders in the offspring across their lifespan. However, the gestational period during which malnutrition exerts a decisive effect is unclear. Brown adipose tissue (BAT) plays a critical role in energy metabolism owing to its high efficiency in oxidizing glucose and fatty acids. This study aimed to determine the impact of maternal high-fat diet (HFD) consumption only during pregnancy on BAT and energy metabolism in offspring mice. Dams were fed an HFD or a normal chow diet from embryonic day 2.5. HFD consumption during pregnancy induced glucose intolerance and hypertension in dams. In the offspring of HFD-fed dams, maternal HFD lowered fetal weight without affecting placental weight, whereas HFD consumption after birth exacerbated oxygen consumption and cold-induced thermogenesis at 12 months of age, accompanied by increased lipid droplet size in BAT. These data demonstrate that HFD consumption only during pregnancy exerts a long-lasting effect on BAT. Collectively, these findings indicate the importance of nutrition during pregnancy with respect to the energy metabolism of the offspring, and pregnant women should thus ensure proper nutrition during pregnancy to ensure normal energy metabolism in the offspring.

Association of Type 2 Deiodinase Thr92Ala Polymorphism with Pediatric Obesity in Japanese Children: A Case-Control Study.

Genetic factors play critical roles in the onset and progression of obesity. Brown adipose tissue (BAT) activity is also critical for adiposity. The objective of this study was to evaluate the prevalence and effects of BAT gene polymorphisms in pediatric obesity. This case-control study included 270 non-obese and 86 obese children. All participants underwent genotyping for type 2 deiodinase (DIO2) Thr92Ala (rs225014). The prevalence of the homozygous Ala/Ala allele of the DIO2 gene in the obese group was 15.1% versus 6.3% in the non-obese group, resulting in an odds ratio (OR) of 3.393 (p = 0.003). The results of this study indicate that the homozygous Ala/Ala allele of the DIO2 gene is associated with an increased risk of pediatric obesity and suggest that pediatric obesity might be suitable for assessing the association with gene polymorphisms related to BAT, especially DIO2 Thr92Ala.

Thyroid hypogenesis is associated with a novel AKT3 germline variant that causes megalencephaly and cortical malformation.

The molecular mechanisms involved in thyroid organogenesis have not been fully elucidated. We report a patient with a de novo germline AKT3 variant, NM_005465.7:c.233A > G, p.(Gln78Arg), who presented with congenital hypothyroidism in addition to typical AKT3-related brain disorders. The report of this patient contributes to delineating the associated yet uncertain endocrine complications of this AKT3 disease-causing variant.

Alfacalcidol improves the growth velocity in children with vitamin D deficiency/insufficiency: A single center retrospective cohort study.

OBJECTIVES: To investigate the growth velocity-improving effects of vitamin D replacement therapy in pediatric patients diagnosed with vitamin D deficiency and insufficiency. STUDY DESIGN: A retrospective cohort study was conducted in 34 pediatric patients diagnosed with vitamin D deficiency/insufficiency. Based on the clinical findings, the subjects were divided into two groups: a bowed leg (BL) group and a non-bowed leg (non-BL) group. After the initiation of alfacalcidol, the standard deviation score (SDS) of their heights, weights and growth velocities in each group were monitored. RESULTS: The median age at the first visit was significantly lesser in the BL group (1.58 years old [interquartile range (IQR): 1.33, 2.17]) than that in the non-BL group (3.00 years old [IQR: 2.33, 3.67]). On the contrary, the SDS for height was significantly lower in the non-BL group (-2.27 [IQR: -2.63, -1.94]) than that in the BL group (-1.37 [IQR: -1.91, -1.07]). One-year treatment with alfacalcidol showed significant improvements in both height SDSs and growth velocity SDSs not only in the BL group but also in the non-BL group. CONCLUSIONS: The current study revealed that vitamin D replacement therapy improved the growth rate in children with vitamin D deficiency/insufficiency, regardless of the presence of BL. This study emphasizes the importance of assessing the vitamin D status in children with poor growth rates and suggests that alfacalcidol could be a valid option for the treatment of short stature.

45,X/46,X,psu idic(Y)(q11.2) in a phenotypically normal male with short stature: a case report.

We report a case of 15-yr-old phenotypically normal male with short stature associated with the chromosomal abnormalities of 46,X,psu idic(Y)(q11.2)/45,X. At 3 yr of age, he underwent urethroplasty for scrotal hypospadias. At 15 yr of age, he was referred to our hospital due to short stature (-3.71 SD). The results of blood examination were mostly normal. A radiological examination revealed his bone age was 15.7 yr (based on the TW2-RUS method). Chromosome analysis of peripheral lymphocytes revealed 46,X,psu idic(Y)(q11.2)[16]/45,X[14], and array comparative genomic hybridization (aCGH) showed a large deletion of Yq which was located distal to the Y chromosome growth-control gene (GCY) region. It is likely that these structural abnormalities in the Y chromosome were responsible for the short stature. This case might provide new insights regarding GCY and emphasizes the importance of chromosome analysis in not only females but also males with short stature, especially when associated with genital anomalies.

ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue.

The angiotensin II (ANG II)-ANG II type 1 receptor (AT1R) axis is a key player in the pathophysiology of obesity. Angiotensin-converting enzyme 2 (ACE2) counteracts the ANG II/AT1R axis via converting ANG II to angiotensin 1-7 (Ang 1-7), which is known to have an anti-obesity effect. In this study, we hypothesized that ACE2 exerts a strong anti-obesity effect by increasing Ang 1-7 levels. We injected intraperitoneally recombinant human ACE2 (rhACE2, 2.0 mg·kg-1·day-1) for 28 days to high-fat diet (HFD)-induced obesity mice. rhACE2 treatment decreased body weight and improved glucose metabolism. Furthermore, rhACE2 increased oxygen consumption and upregulated thermogenesis in HFD-fed mice. In the rhACE2 treatment group, brown adipose tissue (BAT) mass increased, accompanied with ameliorated insulin signaling and increased protein levels of uncoupling protein-1 (UCP-1) and PRD1-BF1-RIZ1 homologous domain containing 16. Importantly, subcutaneous white adipose tissue (sWAT) mass decreased, concomitant with browning, which was established by the increase of UCP-1 expression. The browning is the result of increased H3K27 acetylation via the downregulation of histone deacetylase 3 and increased H3K9 acetylation via upregulation of GCN5 and P300/CBP-associated factor. These results suggest that rhACE2 exerts anti-obesity effects by stimulating BAT and inducing browning in sWAT. ACE2 and the Ang 1-7 axis represent a potential therapeutic approach to prevent the development of obesity.

High-fat diet accelerates extreme obesity with hyperphagia in female heterozygous Mecp2-null mice.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutation of the methyl-CpG-binding protein 2 (MECP2) gene. Although RTT has been associated with obesity, the underlying mechanism has not yet been elucidated. In this study, female heterozygous Mecp2-null mice (Mecp2+/- mice), a model of RTT, were fed a normal chow diet or high-fat diet (HFD), and the changes in molecular signaling pathways were investigated. Specifically, we examined the expression of genes related to the hypothalamus and dopamine reward circuitry, which represent a central network of feeding behavior control. In particular, dopamine reward circuitry has been shown to regulate hedonic feeding behavior, and its disruption is associated with HFD-related changes in palatability. The Mecp2+/- mice that were fed the normal chow showed normal body weight and food consumption, whereas those fed the HFD showed extreme obesity with hyperphagia, an increase of body fat mass, glucose intolerance, and insulin resistance compared with wild-type mice fed the HFD (WT-HFD mice). The main cause of obesity in Mecp2+/--HFD mice was a remarkable increase in calorie intake, with no difference in oxygen consumption or locomotor activity. Agouti-related peptide mRNA and protein levels were increased, whereas proopiomelanocortin mRNA and protein levels were reduced in Mecp2+/--HFD mice with hyperleptinemia, which play an essential role in appetite and satiety in the hypothalamus. The conditioned place preference test revealed that Mecp2+/- mice preferred the HFD. Tyrosine hydroxylase and dopamine transporter mRNA levels in the ventral tegmental area, and dopamine receptor and dopamine- and cAMP-regulated phosphoprotein mRNA levels in the nucleus accumbens were significantly lower in Mecp2+/--HFD mice than those of WT-HFD mice. Thus, HFD feeding induced dysregulation of food intake in the hypothalamus and dopamine reward circuitry, and accelerated the development of extreme obesity associated with addiction-like eating behavior in Mecp2+/- mice.

Erythropoietin and long-acting erythropoiesis stimulating agent ameliorate non-alcoholic fatty liver disease by increasing lipolysis and decreasing lipogenesis via EPOR/STAT pathway.

Erythropoietin (EPO) has been reported to exert a beneficial effect on glucose metabolism in obesity. However, the effect of EPO on lipid metabolism and non-alcoholic fatty liver disease (NAFLD) was unclear. Furthermore, the effect of long acting erythropoiesis stimulating agents (ESA) on metabolism has not been poorly understood. The objective of this study was to investigate the effect of EPO and long acting ESA on NAFLD and lipid metabolism. We administered EPO and darbepoetin alpha (DEPO), a long acting ESA, by intraperitoneally injection for 4 weeks to mice with high-fat-diet (HFD)-induced obesity. EPO and DEPO treatment reduced body weight, ameliorated glucose tolerance and insulin resistance, and prevented lipid accumulation in liver and white adipose tissue (WAT). Administration of EPO and DEPO suppressed lipid synthesis-related protein in liver, including sterol regulatory element-binding protein 1 (SREBP-1), acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS). EPO and DEPO also increased lipolysis protein in visceral WAT, including hormone-sensitive lipase (HSL), atni-adipose triglyceride lipase (ATGL). EPO and DEPO increased phosphorylation signal transducer and activator of transcription 3 (STAT3) and STAT5, transcriptional factors with crucial roles of lipid metabolism. These data suggest that EPO and DEPO ameliorated NAFLD by improving lipid metabolism via EPO/EPOR-induced STAT3 and STAT5 activation. EPO and DEPO may be a therapeutic option for NAFLD.

Decrement in bone mineral density after parathyroidectomy in a pediatric patient with primary hyperparathyroidism.

Primary hyperparathyroidism (PHT) causes increased bone turnover, leading to reduction in bone mineral density (BMD). Parathyroidectomy is a definitive therapy and improves BMD in adult patients with PHT. However, there are no reports regarding alterations of BMD in pediatric or adolescent patients with PHT. Here, we report a case of a 13-yr-old boy with PHT who was referred to our institution for evaluation of hypercalcemia and hyperparathyroidism. Radiological investigation revealed an ectopic parathyroid adenoma below the right thyroid lobe. A minimally invasive radio-guided parathyroidectomy was successfully performed. We followed up the patient's BMD for three years both before and after parathyroidectomy. Over the course of three years, his BMD was steadily decreased, with z-scores of +0.506 at 13 yr and 9 mo, +0.162 at 14 yr and 9 mo, and -0.411 at 15 yr and 9 mo. BMD usually increases during peak height velocity in an adolescent and improves after parathyroidectomy in adult patients with PHT. However, our patient showed decreased BMD z-scores following parathyroidectomy. Therefore, the patient had an increased risk of fracture after parathyroidectomy and was followed up closely. Both height and BMD should be carefully evaluated after parathyroidectomy in pediatric and adolescent patients with PHT.

Angiotensin 1-7 stimulates brown adipose tissue and reduces diet-induced obesity.

The renin-angiotensin system is a key regulator of metabolism with beneficial effects of the angiotensin 1-7 (Ang 1-7) peptide. We hypothesized that the antiobesity effect of Ang 1-7 was related to the stimulation of brown adipose tissue (BAT). We administered Ang 1-7 (0.54 mg kg-1 day-1) for 28 days via implanted micro-osmotic pumps to mice with high-fat diet (HFD)-induced obesity. Ang 1-7 treatment reduced body weight, upregulated thermogenesis, and ameliorated impaired glucose homeostasis without affecting food consumption. Furthermore, Ang 1-7 treatment enlarged BAT and the increased expression of UCP1, PRDM16, and prohibitin. Alterations in PRDM16 expression correlated with increased AMPK and phosphorylation of mTOR. Ang 1-7 treatment elevated thermogenesis in subcutaneous white adipose tissue without altering UCP1 expression. These changes occurred in the context of decreased lipid accumulation in BAT from HFD-fed mice, preserved insulin signaling concomitant with phosphorylation of hormone-sensitive lipase and decreased expression of perilipin. These data suggest that Ang 1-7 induces brown adipocyte differentiation leading to upregulation of thermogenesis and improved metabolic profile in diet-induced obesity. Enhancing Ang 1-7 action represents a promising therapy to increase BAT and to reduce the metabolic complications associated with diet-induced obesity.