The age of the obesity onset is a very important factor for the development of metabolic complications and cardiovascular risk in children and adolescents with severe obesity.

Severe obesity defined as BMI value corresponding to an adult > 40 kg/m2 affects 1-5% of children and adolescents in Europe. The purpose of this study was to assess the occurrence of cardiovascular risk factors in children and adolescents with severe obesity. The analysis included 140 patients (75 female) at the mean age of 14 ± 2.1 SD (range 10-18) years (all recruited in 4 regional reference centers in Poland). Severe obesity was defined as BMI > 35 kg/m2 (children 6-14 years), and BMI > 40 kg/m2 (> 14 years). Fasting plasma samples have been obtained in all patients, and OGTT was performed in all patients. The metabolic risk factors were defined as high blood pressure (BP > 90 percentile for height, age, and sex), HDL cholesterol < 1.03 mmol/L, TG ≥ 1.7 mmol/L, and hyperglycemic state (fasting blood glucose > 5.6 mmol/L, or blood glucose 120' after oral glucose load > 7.8 mmol/L). Additionally, the MetS z-score was calculated using Metabolic Syndrome Severity Calculator. One hundred twenty-four (89%) participants presented with high BP, 117 (84%) with abnormal lipid profile, and 26 with the hyperglycemic. Only 12 (9%) were free of metabolic complications. More than 60% of patients had more than one cardiovascular risk factor. The high BP was significantly associated with the severity of obesity (F = 9.9, p = 0.002). Patients with at least one metabolic complication presented with significantly younger age of the onset of obesity (the mean age of the patients with no overt obesity complications was 10 years, while the mean age of those who presented at least one was 4.7 ± 3.5 SD years (p = 0.002)). A significant positive association between in the value of the Mets BMI z-score with age was observed (R = 0.2, p < 0.05). There were no differences between girls and boys regarding Mets BMI z-score (1.7 ± 0.8 vs 1.7 ± 0.7, p = 0.8).Conclusions: The most common metabolic risk factor in children and adolescents with severe obesity was high BP. The most important factor determining presence of obesity complications, and thus the total metabolic risk, seems to be younger (< 5 years) age of onset of obesity. What is Known? • It is estimated that 1-5% of children and adolescents in Europe suffer from severe obesity corresponding to an adult BMI > 40 kg/m2, and it is the fastest growing subcategory of childhood obesity. • Children with severe obesity face substantial health risk that may persist into adulthood, encompassing chronic conditions, psychological disorders and premature mortality. What is new: • The most common complication is high BP that is significantly associated with the severity of obesity (BMI z-score), contrary to dyslipidemia and hyperglycemic state, which do not depend on BMI z-score value. • The most important factor determining presence of obesity complications, and thus the total metabolic risk, seems to be younger (< 5 years) age of onset of obesity.

Is nuchal translucency of 3.0-3.4 mm an indication for cfDNA testing or microarray? - a multicenter retrospective clinical cohort study.

INTRODUCTION: This study aimed to evaluate the occurrence of clinically relevant (sub)microscopic chromosomal aberrations in fetuses with the NT range from 3.0 to 3.4 mm, which would be potentially missed by cfDNA testing. METHODS: A retrospective data analysis of 271 fetuses with NT between 3.0 and 3.4 mm and increased combined test (CT) risk in five cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed. RESULTS: A chromosomal aberration was identified in 18.8% fetuses (1:5; 51/271). In 15% (41/271) of cases trisomy 21, 18, or 13 was found. In 0.7% (2/271) sex chromosome aneuploidy was found. In 1.1% (3/271) of cases, CNV>10Mb was detected, which would potentially also be detected by genome-wide cfDNA testing. The residual risk for missing a submicroscopic chromosome aberration in the presented cohorts is 1.8% (1:54; 5/271). CONCLUSION: Our results indicate that a significant number of fetuses with increased CT risk and presenting NT of 3.0-3.4 mm carry a clinically relevant chromosomal abnormality other than common trisomy. Invasive testing should be offered and counseling on NIPT should include the test limitations that may result in NIPT false negative results in a substantial percentage of fetuses.

Genetic Profiling in Children With Acute Lymphoblastic Leukemia Referred for Allogeneic Hematopoietic Stem Cell Transplantation.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is the essential and often the only curative therapeutic option in high risk and relapsed pediatric acute lymphoblastic leukemia (ALL). METHODS: The objective of the study was to investigate whole-genome expression in children with high risk or relapsed ALL referred for HSCT. Gene expression was assessed in 18 children with ALL referred for HSCT (10 high risk, 8 relapsed; median age of 9.4 years) and in a control group of 38 obese children (median age of 14.1 years). Whole-genome expression was assessed in leukocytes using GeneChip® HumanGene 1.0 ST microarray. RESULTS: The analysis of genomic profiles revealed a significantly lower expression of 21 genes with a defined function, involved in immunoglobulin production, lymphocyte function, or regulation of DNA processing in ALL patients referred for HSCT compared with the control group. CONCLUSION: Genome expression of patients with ALL in remission referred to HSCT revealed deep immunosuppression of both B-cell and T-cell lineages, which may increase the probability of donor cell engraftment.

Transcriptome analysis reveals dysregulation of genes involved in oxidative phosphorylation in a murine model of retinopathy of prematurity.

BACKGROUND: Retinal gene expression pattern is severely altered after exposition to hyperoxia in mice with oxygen-induced retinopathy (OIR), a common model of retinopathy of prematurity. Gene ontology and signaling pathway analyses may add new insights into a better understanding of the pathogenesis of this disease. METHODS: Seven-day-old C57BL/6J mice (n = 60) were exposed to 75% oxygen for 5 days and then recovered in room air. The controls (n = 60) were kept in the normoxic conditions. Retinas were harvested immediately following hyperoxia, during the phase of maximal neovascularization, and at the time of neovascularization regression. The retinal RNA samples were evaluated for gene expression using mouse gene expression microarrays. DAVID annotation tools were used for gene ontology and pathway analyses. RESULTS: The most significantly enriched signaling pathways during the neovascularization phase of OIR were: focal adhesion; ECM-receptor interaction; PI3K-Akt; oxidative phosphorylation; and Alzheimer's, Parkinson's and Huntington's disease signaling pathways. Genes involved in apoptosis, cell proliferation, cell differentiation, and immune responses were associated with neovascularization regression. CONCLUSIONS: Performed analyses revealed the possible involvement of various signaling pathways in OIR pathomechanism, mostly specific to the OIR phase. Dysregulation of genes involved in oxidative phosphorylation may have an impact on neovascularization development.

Short- and long-term impact of hyperoxia on the blood and retinal cells' transcriptome in a mouse model of oxygen-induced retinopathy.

BACKGROUND: We aimed to identify global blood and retinal gene expression patterns in murine oxygen-induced retinopathy (OIR), a common model of retinopathy of prematurity, which may allow better understanding of the pathogenesis of this severe ocular prematurity complication and identification of potential blood biomarkers. METHODS: A total of 120 C57BL/6J mice were randomly divided into an OIR group, in which 7-day-old pups were maintained in 75% oxygen for 5 days, or a control group. RNA was extracted from the whole-blood mononuclear cells and retinal cells on days 12, 17, and 28. Gene expression in the RNA samples was evaluated with mouse gene expression microarrays. RESULTS: There were 38, 1370 and 111 genes, the expression of which differed between the OIR and control retinas on days 12, 17, and 28, respectively. Gene expression in the blood mononuclear cells was significantly altered only on day 17. Deptor and Nol4 genes showed reduced expression both in the blood and retinal cells on day 17. CONCLUSION: There are sustained marked changes in the global pattern of gene expression in the OIR mice retinas. An altered expression of Deptor and Nol4 genes in the blood mononuclear cells requires further investigation as they may indicate retinal neovascularization.

Case report of endoprosthesis -Y implantation in severe respiratory failure in the MPSII patient; comparison with literature data.

BACKGROUND: The tracheobronchomalacia is a life-threatening complication of mucopolysaccharidosis (MPS) without known effective, optimal treatment. The severe expiratory collapse of the trachea and bronchi is one of causes of the high rate of deaths in the course of airway impairment in MPSII patients. CASE PRESENTATION: Due to the adynamic tracheobronchomalacia despite of enzymatic treatment (ERT) in our MPSII patient, a life-saving tracheal bifurcated type-Y endoprosthesis (a self-expanding, metal stent for the prosthesis of tracheal and bronchial stenosis) was implanted. In the followed months, the breathing efficiency improved, but then gradual worsening, progression of bronchi occlusion at the stent border resulted in patient's death. CONCLUSION: The Y-stent implantation appears to be a short-term, life-saving solution without satisfactory long-term effects due to the progress of peripheral bronchomalacia and increased tissue proliferation and granulation, that arises during the illness' course.

Neurodegenerative changes detected by neuroimaging in a patient with contiguous X-chromosome deletion syndrome encompassing BTK and TIMM8A genes.

INTRODUCTION: In this study we describe a patient with gross deletion containing the BTK and TIMM8A genes. Mutations in these genes are responsible for X-linked agammaglobulinemia and Mohr-Tranebjaerg syndrome, respectively. X linked agammaglobulinemia is a rare primary immunodeficiency characterized by low levels of B lymphocytes and recurrent microbial infections, whereas, Mohr-Tranebjaerg syndrome is a progressive neurodegenerative disorder with early onset of sensorineural deafness. MATERIAL AND METHODS: For neuroimaging, the magnetic resonance imaging and magnetic resonance spectroscopy of the brain were performed. Microarray analysis was performed to establish the extent of deletion. RESULTS: The first clinical symptoms observed in our patient at the age of 6 months were connected with primary humoral immunodeficiency, whereas clinical signs of MTS emerged in the third year of live. Interestingly, the loss of speech ability was not accompanied by hearing failure. Neuroimaging of the brain suggested leukodystrophy. Molecular tests revealed contiguous X-chromosome deletion syndrome encompassing BTK (from exons 6 through 19) and TIMM8A genes. The loss of the patient's DNA fragment was accurately localized from 100 601 727 to 100 617 576 bp on chromosome's loci Xq22.1. CONCLUSIONS: We diagnosed XLA-MTS in the first Polish patient on the basis of particular molecular methods. We detected neurodegenerative changes in MRI and MR spectroscopy in this patient. Our results provide further insight into this rare syndrome.

Intima media thickness of common carotids and abdominal aorta in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in relation to their genotypes.

BACKGROUND: Patients with congenital adrenal hyperplasia (CAH) are at risk of vascular and metabolic complications due to steroid therapy and increased adrenal androgens exposure. OBJECTIVE: of the study was to evaluate the relation between patient's genotype and (1) intima media thickness of abdominal aorta (AIMT) and common carotid arteries (CIMT) and (2) metabolic profile. MATERIAL AND METHODS: In 71 patients (27 boys) aged from 1.5 to 17.9 years, with 21-hydroxylase deficiency (21OHD) CAH: 9 with nonclassic (NC) CAH, 62 with classic CAH: 10 with simple virilising (SV) and 52 with salt wasting (SW) CAH (13-Del/Del, 8-Del/I2G, 7-I2G/I2G and 24-other genotypes), and in 77 lean and 36 normotensive obese, age and gender matched controls, assessment of CIMT and AIMT as well as hormonal and biochemical evaluation were performed. RESULTS: The highest AIMT was observed in SW Del/Del and I2G/I2G groups and the highest CIMT in SV CAH subgroup. CIMT and AIMT correlated significantly with testosterone and free androgen index (FAI), and were significantly higher in patients with advanced bone age and obesity independent. Significantly higher HOMA, testosterone and FAI values were found in SV CAH. CONCLUSION: In CAH patients CIMT and AIMT are influenced by androgens and obesity independent. In the examined group vascular and metabolic abnormalities are pronounced more in certain subgroups of CAH (SV and SW: Del/Del) and in patients with advanced bone age.

Circadian blood pressure profiles and ambulatory arterial stiffness index in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in relation to their genotypes.

OBJECTIVE: Lifelong steroid therapy and exposure to adrenal androgen excess in 21-hydroxylase deficient (21-OHD) congenital adrenal hyperplasia (CAH) children and adolescents may modify circadian blood pressure profile and result in vascular complications. The objective of the study was to evaluate vascular abnormalities in 21-OHD children and adolescents in relation to their genotypes. DESIGN: A cross-sectional study conducted at a tertiary referral center. PATIENTS: Seventy patients with 21-OHD CAH (27 boys), aged from 3 to 17.9 years: 9 with nonclassic CAH, 61 with classic CAH: 10 with simple virilising (SV) and 51 with salt wasting CAH (13-Del/Del, 8-Del/I2G, 7-I2G/I2G and 23-other genotypes). MAIN OUTCOMES MEASURES: The assessment of systolic and diastolic BP (SBP, DBP) loads, night dip% and arterial ambulatory stiffness index (AASI) in 21-OHD CAH patients.

Comparison of whole genome expression profile between preterm and full-term newborns.

OBJECTIVES: Evaluate the time dependent expression of genes in preterm neonates and verify the influence of ontogenic maturation and the environmental factors on the gene expression after birth. MATERIAL AND METHODS: The study was carried out on 20 full-term newborns and 62 preterm newborns (mean birth weight = 1002 [g] (SD: 247), mean gestational age = 27.2 weeks (SD: 1.9)). Blood samples were drawn from all the study participants at birth and at the 36th week postmenstrual age from the preterm group to assess whole genome expression in umbilical cord blood and in peripheral blood leukocytes, respectively. (SurePrint G3 Human Gene Expression v3, 8x60K Microarrays (Agilent)). RESULTS: A substantial number of genes was found to be expressed differentially at the time of birth and at 36 PMA in comparison to the term babies with more genes being down-regulated than up-regulated. However, the fold change in the majority of cases was < 2.0. Extremely preterm and very preterm infants were characterized by significantly down-regulated cytokine and chemokine related pathways. The number of down-regulated genes decreased and number of up-regulated genes increased at 36 PMA vs. cord blood. There were no specific gene expression pathway profiles found within the groups of different gestational ages. CONCLUSIONS: Preterm delivery is associated with a different gene expression profile in comparison to term delivery. The gene expression profile changes with the maturity of a newborn measured by the gestational age.

Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior.

Microvesicles (MVs) are membrane-enclosed cytoplasmic fragments released by normal and activated cells that have been described as important mediators of cell-to-cell communication. Although the ability of human induced pluripotent stem cells (hiPSCs) to participate in tissue repair is being increasingly recognized, the use of hiPSC-derived MVs (hiPSC-MVs) in this regard remains unknown. Accordingly, we investigated the ability of hiPSC-MVs to transfer bioactive molecules including mRNA, microRNA (miRNA), and proteins to mature target cells such as cardiac mesenchymal stromal cells (cMSCs), and we next analyzed effects of hiPSC-MVs on fate and behavior of such target cells. The results show that hiPSC-MVs derived from integration-free hiPSCs cultured under serum-free and feeder-free conditions are rich in mRNA, miRNA, and proteins originated from parent cells; however, the levels of expression vary between donor cells and MVs. Importantly, we found that transfer of hiPSC components by hiPSC-MVs impacted on transcriptome and proteomic profiles of target cells as well as exerted proliferative and protective effects on cMSCs, and enhanced their cardiac and endothelial differentiation potential. hiPSC-MVs also transferred exogenous transcripts from genetically modified hiPSCs that opens new perspectives for future strategies to enhance MV content. We conclude that hiPSC-MVs are effective vehicles for transferring iPSC attributes to adult somatic cells, and hiPSC-MV-mediated horizontal transfer of RNAs and proteins to injured tissues may be used for therapeutic tissue repair. In this study, for the first time, we propose a new concept of use of hiPSCs as a source of safe acellular bioactive derivatives for tissue regeneration.

Transcriptome profiling of the newborn mouse brain after hypoxia-reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes.

BACKGROUND: Supplemental oxygen used during resuscitation can be detrimental to the newborn brain. The aim was to determine how different oxygen therapies affect gene transcription in a hypoxia-reoxygenation model. METHODS: C57BL/6 mice (n = 56), postnatal day 7, were randomized either to 120 min of hypoxia 8% O2 followed by 30 min of reoxygenation with 21, 40, 60, or 100% O2, or to normoxia followed by 30 min of 21 or 100% O2. Affymetrix 750k expression array was applied with RT-PCR used for validation. Histopathology and immunohistochemistry 3 d after hypoxia-reoxygenation compared groups reoxygenated with 21 or 100% O2 with normoxic controls (n = 22). RESULTS: In total, ~81% of the gene expression changes were altered in response to reoxygenation with 60 or 100% O2 and constituted many inflammatory-responsive genes (i.e., C5ar2, Stat3, and Ccl12). Oxidative phosphorylation was downregulated after 60 or 100% O2. Iba1(+) cells were significantly increased in the striatum and hippocampal CA1 after both 21 and 100% O2. CONCLUSION: In the present model, hypoxia-reoxygenation induces microglial accumulation in subregions of the brain. The transcriptional changes dominating after applying hyperoxic reoxygenation regimes include upregulating genes related to inflammatory responses and suppressing the oxidative phosphorylation pathway.

Comparison of clinical characteristics of a pediatric cohort with combined pituitary hormone deficiency caused by mutation of the PROP1 gene or of other origins.

The most commonly identified genetic cause of combined pituitary hormone deficiency (CPHD) is PROP1 gene mutations. The aim of the study was to compare selected clinical features of patients with CPHD caused by variants of the PROP1 gene (CPHD-PROP1) and patients with inborn CPHD of other etiology (CPHD-nonPROP1). MATERIAL AND METHODS: The retrospective analysis included childhood medical records of 74 patients (32 female) with CPHD, including 43 patients (23 female) with the mutation in the PROP1 gene. RESULTS: Patients with CPHD-PROP1 compared to the CPHD-nonPROP1 presented with the following: significantly higher median birth weight (0.21 vs. - 0.29 SDS, p = 0.019), lower growth velocity within 3 years preceding growth hormone administration (- 2.7 vs. - 0.8 SDS, p < 0.001), higher mean maximal blood concentration of growth hormone within the stimulation process (1.2 vs. 1.08 ng/mL, p = 0.003), lower TSH (1.8 vs. 2.4 µIU/mL, p < 0.001), significantly lower prolactin concentrations (128 vs. 416.3 µIU/mL, p < 0.001), and less frequent typical signs of hypogonadism at birth in boys (n = 6; 30% vs. n = 12, 54%, p < 0.001). Secondary adrenal insufficiency was less frequent in CPHD-PROP1 (20 vs. 25 cases, p = 0.006) and occurred at a later age (13.4 vs. 10.4 years). MRI of the pituitary gland in CPHD-PROP1 revealed a small pituitary gland (21 cases), pituitary gland enlargement (eight cases), and one pituitary stalk interruption and posterior lobe ectopy, while it was normal in nine cases. CONCLUSION: Patients with the PROP1 mutations present a clinical picture significantly different from that of other forms of congenital hypopituitarism. Certain specific clinical results may lead to the successful identification of children requiring diagnostics for the PROP1 gene mutation.

New insight into the pathogenesis of retinopathy of prematurity: assessment of whole-genome expression.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the most common preventable causes of blindness and impaired vision among children in developed countries. The aim of the study was to compare whole-genome expression in the first month of life in groups of infants with and without ROP. METHODS: Blood samples were drawn from 111 newborns with a mean gestational age of 27.8 wk on the 5th, 14th, and 28th day of life (DOL). The mRNA samples were evaluated for gene expression with the use of human whole-genome microarrays. The infants were divided into two groups: no ROP (n = 61) and ROP (n = 50). RESULTS: Overall, 794 genes were differentially expressed on the 5th DOL, 1,077 on the 14th DOL, and 3,223 on the 28th DOL. In each of the three time points during the first month of life, more genes were underexpressed than overexpressed in the ROP group. Fold change (FC), which was used in analysis of gene expression data, ranged between 1.0 and 1.5 in the majority of genes differentially expressed. CONCLUSION: Pathway enrichment analysis revealed that genes in four pathways related to inflammatory response were consistently downregulated due to the following variables: ROP and gestational age.

Transcriptome profiling of the newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation affects mTOR signaling pathway, DNA repair, and JNK-pathway regulation.

BACKGROUND: The use of oxygen in acute treatment of asphyxiated term newborns is associated with increased mortality. It is unclear how hyperoxic reoxygenation after hypoxia affects transcriptional changes in the newborn lung. METHODS: On postnatal day 7, C57BL/6 mice (n = 62) were randomized to 120-min hypoxia (fraction of inspired oxygen (FiO2) 0.08) or normoxia. The hypoxia group was further randomized to reoxygenation for 30 min with FiO2 0.21, 0.40, 0.60, or 1.00, and the normoxia group to FiO2 0.21 or 1.00. Transcriptome profiling was performed on homogenized lung tissue using the Affymetrix 750k expression array, and validation was carried out by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: The hypoxia-reoxygenation model induced hypoxia-inducible factor 1 (HIF-1) targets like Vegfc, Adm, and Aqp1. In total, ~70% of the significantly differentially expressed genes were detected in the two high hyperoxic groups (FiO2 0.60 and 1.00). Reoxygenation with 100% oxygen after hypoxia uniquely upregulated Gadd45g, Dusp1, Peg3, and Tgm2. Pathway analysis identified mammalian target of rapamycin (mTOR) signaling pathway, DNA repair, c-jun N-terminal kinase (JNK)-pathway regulation, and cell cycle after hyperoxic reoxygenation was applied. CONCLUSION: Acute hypoxia induces HIF-1 targets independent of the reoxygenation regime applied. Hyperoxic reoxygenation affects pathways regulating cell growth and survival. DNA-damage-responsive genes are restricted to reoxygenation with 100% oxygen.

Impact of antenatal glucocorticosteroids on whole-genome expression in preterm babies.

AIM: To study the impact that using antenatal steroid to treat threatened preterm delivery has on whole-genome expression. METHODS: A prospective whole-genome expression study was carried out on 50 newborn infants, delivered before 32 weeks gestation, who had been exposed to antenatal steroids, including 40 who had received a full antenatal steroid course. Seventy infants not exposed to antenatal steroids formed the control group. Microarray analyses were performed five and 28 days after delivery, and the results were validated by real-time PCR. The study was conducted between September 2008 and November 2010. RESULTS: Twenty thousand six hundred and ninety-three genes were studied in the infants' leucocytes. Thirteen were differentially expressed 5 days after delivery, but there were no differences at day 28. Four genes related to cancer or inflammation were up-regulated. Nine genes were down-regulated: six were Y-linked and associated with malignancies, graft-versus-host disease, male infertility and cell differentiation and three were associated with pre-eclampsia, oxidative stress and chloride/bicarbonate exchange. Seven gene pathways were up-regulated at day five and only one at day 28. These were associated with cell growth, cell cycle regulation, metabolism and apoptosis. CONCLUSION: Antenatal steroid therapy affects a limited number of genes and gene pathways in leucocytes in preterm babies at day five of life. The effect is short-lived, but long-term effects cannot be ruled out.

Analysis of miRNAs in Osteogenesis imperfecta Caused by Mutations in COL1A1 and COL1A2: Insights into Molecular Mechanisms and Potential Therapeutic Targets.

Osteogenesis imperfecta (OI) is a group of connective tissue disorders leading to abnormal bone formation, mainly due to mutations in genes encoding collagen type I (Col I). Osteogenesis is regulated by a number of molecules, including microRNAs (miRNAs), indicating their potential as targets for OI therapy. The goal of this study was to identify and analyze the expression profiles of miRNAs involved in bone extracellular matrix (ECM) regulation in patients diagnosed with OI type I caused by mutations in COL1A1 or COL1A2. Primary skin fibroblast cultures were used for DNA purification and sequence analysis, followed by analysis of miRNA expression. Sequencing analysis revealed mutations of the COL1A1 or COL1A2 genes in all OI patients, including four previously unreported. Amongst the 40 miRNAs analyzed, 9 were identified exclusively in OI cells and 26 in both OI patients and the controls. In the latter case, the expression of six miRNAs (hsa-miR-10b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, has-miR-204-5p, has-miR-216a-5p, and hsa-miR-449a) increased, while four (hsa-miR-129-5p, hsa-miR-199b-5p, hsa-miR-664a-5p, and hsa-miR-30a-5p) decreased significantly in OI cells in comparison to their expression in the control cells. The identified mutations and miRNA expression profiles shed light on the intricate processes governing bone formation and ECM regulation, paving the way for further research and potential therapeutic advancements in OI and other genetic diseases related to bone abnormality management.

Management precautions for risk of obesity are necessary among infants with PKU carrying the rs113883650 variant of the LAT1 gene: A cross-sectional study.

Patients with phenylketonuria (PKU), an inborn error of phenylalanine metabolism, require consistent treatment to avoid the brain toxicity caused by hyperphenylalaninemia. The treatment consists of life-long use of a low-phenylalanine diet, which aims at decreasing hyperphenylalaninemia and maintaining blood phenylalanine concentration in a safe range. Problems with balancing diet can result in suboptimal treatment outcomes; however, recent findings suggest that genetic alteration of the transport of phenylalanine might result in an additional health burden. We assessed the effect of a common variant (rs113883650) of the LAT1(SLC7A5) gene, which encodes the main transmembrane phenylalanine transporter, on the development of overweight in 54 infants with PKU who received standard therapy and adhered well to therapeutic prescriptions, and in 55 infants with a milder disease form-the so-called mild hyperphenylalaninemia (MHP), which does not require treatment. We found that infants with PKU-carriers of the rs113883650 variant had significantly higher Body Mass Index (BMI) at 1 year compared to PKU infants without the variant (mean BMI Z-Score of +1.15 SD vs -0.15 SD, respectively; t(52) = 5.25, p = 0.00005). Conversely, no significant BMI differences were detected in the subgroups of infants with MHP (t(53) = 1.15, p = 0.25). Additionally, high BMI in infants with PKU-carriers of the rs113883650 variant positively correlated with high variability of their blood phenylalanine levels (r(52) = 0.42, p = 0.002). It should be noted that this is an observational study, which does not determine causation. Nevertheless, our findings show that the rs113883650 variant of the LAT1 gene may be a risk factor for overweight in properly treated infants with PKU. Management precautions should be taken to prevent the development of overweight and obesity.

Cardiovascular Anomalies among 1005 Fetuses Referred to Invasive Prenatal Testing-A Comprehensive Cohort Study of Associated Chromosomal Aberrations.

This retrospective cohort study comprehensively evaluates cardiovascular anomalies (CVAs) and associated extracardiac structural malformations (ECMs) among 1005 fetuses undergoing invasive prenatal testing at a single tertiary Polish center in the context of chromosomal aberrations detected in them by array comparative genomic hybridization (aCGH) and G-band karyotyping. The results of our study show that CVAs are among the most common malformations detected in fetuses undergoing invasive prenatal testing, as they affected 20% of all cases seen in our department. Septal defects predominated among fetuses with numerical aberrations, while conotruncal defects were the most common findings among fetuses with pathogenic copy number variants (CNVs). In 61% of cases, CVAs were associated with ECMs (the diagnosis was confirmed postnatally or in cases of pregnancy termination by means of autopsy). The most common ECMs were anomalies of the face and neck, followed by skeletal defects. In total, pathogenic chromosomal aberrations were found in 47.5% of CVAs cases, including 38.6% with numerical chromosomal aberrations. Pathogenic CNVs accounted for 14.5% of cases with CVAs and normal karyotype. Thus, our study highlights the importance of assessing the anatomy of the fetus, and of the genetic testing (preferably aCGH) that should be offered in all CVA and ECM cases.