Effect of Previous Alkylating Agent Exposure on Follicle Numbers in Cryopreserved Prepubertal and Young Adult Ovarian Tissue after Long-Term Xenografting

Purpose and methods: To elucidate whether previous cancer treatment affects graft recovery and follicle numbers, morphology, and development in grafts, cryopreserved ovarian biopsies obtained from 18 cancer patients aged 1–24 years with and without exposure to chemotherapy were xenografted as 1 mm3 fragments to immunodeficient mice for 22 weeks with exogenous stimulation. Results: Graft recovery showed no association with chemotherapy exposure, pubertal stage, or leukemia contamination. Total follicle number per recovered graft varied between 0 and 1031 in the chemotherapy-exposed and between 0 and 502 in the non-chemotherapy-exposed group. Atretic follicles formed the largest proportion of the follicle pool in chemotherapy-exposed grafts. Increased atresia correlated with exposure to alkylating agents (mean ± SD 8866.2 ± 9316.3 mg/m2) but not with anthracyclines, pubertal stage, or leukemia contamination. Conclusion: The observation confirms the harmful effects of alkylating agents on ovarian tissue. Therapy at the median cumulative dose of 8866 mg/m2 leads to the decreased quality of cryopreserved ovarian follicles in children and young adults.

Genomic Identification, Evolution, and Expression Analysis of Bromodomain Genes Family in Buffalo

Bromodomain (BRD) is an evolutionarily conserved protein–protein interaction module that is critical in gene regulation, cellular homeostasis, and epigenetics. This study aimed to conduct an identification, evolution, and expression analysis of the BRD gene family in the swamp buffalo (Bubalus bubalis). A total of 101 BRD protein sequences deduced from 22 BRD genes were found in the buffalo genome. The BRD proteins were classified into six groups based on phylogenetic relationships, conserved motifs, and conserved domains. The BRD genes were irregularly distributed in 13 chromosomes. Collinearity analysis revealed 20 BRD gene pairs that had remarkable homologous relationships between the buffalo and cattle, although no tandem or segmental duplication event was found in the buffalo BRD genes. Comparative transcriptomics using a 10x sequencing platform analysis showed that 22 BRD genes were identified in the Sertoli cells (SCs) at different developmental stages of buffalo. Further, the mRNA expression levels of bromodomain and the extraterminal (BET) family in SCs at the pubertal stage were higher than that at the prepubertal stage of buffalo. However, the SMARCA2, PHIP, BRD9, and TAF1 genes exhibited the opposite trend. The maturation process of SCs may be regulated by the BRD family members expressed differentially in SCs at different developmental stages of buffalo. In summary, our findings provide an understanding of the evolutionary, structural, and functional properties of the buffalo BRD family members, and further characterize the function of the BRD family in the maturation of SCs. It also provides a theoretical basis for further understanding in the future of the mechanism of SCs regulating spermatogenesis.

Comparison of facemask therapy effects using skeletal and tooth-borne anchorage:

ABSTRACT Objectives To investigate long-term outcomes of dentoskeletal changes induced by facemask therapy using skeletal anchorage in Class III patients and compare them to those of conventional tooth-borne anchorage. Materials and Methods This retrospective study included 20 patients who received facemask (FM) therapy with miniplates as anchorage for maxillary protraction (Miniplate/FM group, 10.6 ± 1.1 years old [mean ± SD]) and 23 patients who were treated with facemask with rapid maxillary expander (RME/FM group, 10.0 ± 1.5 years old [mean ± SD]). Dentoskeletal changes were evaluated using lateral cephalograms at pretreatment (T1), after facemask therapy (T2), and at the post-pubertal stage (T3). Cephalometric changes were compared between groups and clinical success rates at T3 were evaluated. Results SNA and A to N perpendicular to FH increased significantly more in the Miniplate/FM group than in the RME/FM group when comparing short-term effects of facemask therapy (T1–T2). ANB, Wits appraisal, Angle of convexity, mandibular plane angle, and overjet decreased significantly more in the RME/FM group than in the Miniplate/FM group after facemask therapy (T2–T3). A more favorable intermaxillary relationship was observed in the Miniplate/FM group than in the RME/FM group in long-term observations (T1–T3). Clinical success rate at T3 was 95% in the Miniplate/FM group and 85% in the RME/FM group. Conclusions Facemask therapy with skeletal anchorage showed a greater advancement of the maxilla and more favorable stability for correction of Class III malocclusion in the long-term than conventional facemask therapy with tooth-borne anchorage.

The Vitamin D Decrease in Children with Obesity Is Associated with the Development of Insulin Resistance during Puberty: The PUBMEP Study

Obesity and cardiometabolic risk have been associated with vitamin D levels even in children. The objective of the present study was to evaluate the association between insulin resistance (IR), cardiometabolic risk factors, and vitamin D in children from prepubertal to pubertal stages. A total of 76 children from the PUBMEP study, aged 4–12 years at baseline, were included. Children were evaluated in prepubertal and pubertal stages. Anthropometric measurements and selected cardiometabolic risk biomarkers, such as plasma glucose, blood lipids, insulin, adiponectin, leptin, and blood pressure, and serum 25-hydroxyvitamin D (25(OH)D) were determined. Children were categorized by obesity degree and IR status combined before and after puberty. Paired t-test and multivariate linear regression analyses were conducted. During puberty, the increase in triacylglycerols, insulin, and HOMA-IR and the decrease in QUICKI were significantly associated with the reduction in 25(OH)D (B = −0.274, p = 0.032; B = −0.219, p = 0.019; B = −0.250, p = 0.013; B = 1.574, p = 0.013, respectively) after adjustment by BMI-z, sex, and pubertal stage. Otherwise, prepubertal non-IR children with overweight/obesity that became IR during puberty showed a significant decrease in 25(OH)D and HDL-c, and an increase in waist circumference and triacylglycerol concentrations (p < 0.05 for all) over time. These results suggest that changes in IR seem to be associated with an effect on 25(OH)D levels during puberty, especially in children with overweight.

Adipocytokines on Insulin Resistance in Adolescents

Background: Recently, leptin/adiponectin (L/A) ratio has been suggested as a novel predictor of cardio-metabolic and other chronic disease.Aim: to evaluate the ability of leptin (L), adiponectin (A) and the L/A ratio in identifying high risk of IR in adolescents adjusted by cardiorespiratory fitness, adherence to the Mediterranean diet and body fat percentage. Subjects and methods: This is a cross-sectional analysis with 529 adolescents aged 12-18 years-old. Blood samples were taken to analyze glucose, insulin, leptin, and adiponectin levels. IR (homeostasis model assessment of insulin resistance [HOMA‐IR] was estimated from fasting serum insulin and glucose). Results: Adiponectin, leptin, and L/A ratio were accurate to predict of IR among adolescents. The optimal L/A cut-off value to indicate risk of IR development was >0.35 in boys and >0.97 in girls. Logistic analyses showed that the suggested cut points for adiponectin (girls: OR:2.87 (1.1.26-6.53); p=0.012); leptin (boys: OR:5.23 (1.16-7.14) p = 0.006; girls: OR:2.99 (1.10-8.09) p=0.031) and the L/A ratio (boys: OR:8.38 (2.6-26.8) p<0.001; girls: OR:6.1 (2.1-17.0) p<0.001), were significant predictors of IR, after adjustments for age, pubertal stage, adherence to the Mediterranean diet, cardiorespiratory fitness and body fat percentage. Conclusion: Leptin and L/A ratio were associated with IR risk, after adjustments for confounders in both sexes and adiponectin in girls. L/A ratio seems to have a higher diagnostic accuracy to identify IR risk than adiponectin or leptin, in both sexes.

Clinical Utility of Anti-Mullerian Hormone in Pediatrics

Context Anti-Mullerian Hormone (AMH) was originally described in the context of sexual differentiation in the male fetus but has gained prominence now as a marker of ovarian reserve and fertility in females. In this mini review, we offer an updated synopsis on AMH and its clinical utility in pediatric patients. Design and Results A systematic search was undertaken for studies related to the physiology of AMH, normative data and clinical role in pediatrics. In males, AMH, secreted by Sertoli cells, is found at high levels prenatally and throughout childhood and declines with progression through puberty to overlap with levels in females. Thus, serum AMH has clinical utility as a marker of testicular tissue in males with differences in sexual development, cryptorchidism and in the evaluation of persistent Mullerian duct syndrome. In females, serum AMH has been used as a predictive marker of ovarian reserve and fertility, but pre-pubertal and adolescent AMH assessments need to be interpreted cautiously. AMH is also a marker of tumor burden, progression, and recurrence in germ cell tumors of the ovary. Conclusions AMH has widespread clinical diagnostic utility in pediatrics but interpretation is often challenging and should be undertaken in the context of not only age and sex, but also developmental and pubertal stage of the child. Non-standardized assays necessitate the need for assay-specific normative data. The recognition of the role of AMH beyond gonadal development and maturation may usher in novel diagnostic and therapeutic applications that would further expand its utility in pediatric care.

Unique plasma metabolite signature for adolescents with Klinefelter syndrome reveals altered fatty acid metabolism

Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS). The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 yrs), pubertal stage, and body mass index z-score (0.1 ± 1.2), and then between testosterone treated (n=16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (AUC>0.9, p<0.0001). Multiple saturated free fatty acids were higher in KS while mono- and polyunsaturated fatty acids were lower, and the top significantly enriched pathway was mitochondrial β-oxidation of long-chain saturated fatty acids (enrichment ratio 16, p<0.0001). In contrast, there were no observed differences in metabolite concentrations between testosterone-treated and untreated individuals with KS. In conclusion, the plasma metabolome profile in adolescent males with KS is distinctly different from males without KS independent of age, obesity, pubertal development, or testosterone treatment status, and is suggestive of differences in mitochondrial β-oxidation.