Publications by authors named "Jacek J Pietrzyk"

71 Publications

Immune System Regulation Affected by a Murine Experimental Model of Bronchopulmonary Dysplasia: Genomic and Epigenetic Findings.

Neonatology 2019 27;116(3):269-277. Epub 2019 Aug 27.

Department of Pediatric Research, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.

Background: Bronchopulmonary dysplasia (BPD) is a common cause of abrupted lung development after preterm birth. BPD may lead to increased rehospitalization, more severe and frequent respiratory infections, and life-long reduced lung function. The gene regulation in lungs with BPD is complex, with various genetic and epigenetic factors involved.

Objectives: The aim of this study was to examine the regulatory relation between gene expression and the epigenome (DNA methylation) relevant for the immune system after hyperoxia followed by a recovery period in air using a mouse model of BPD.

Methods: Newborn mice pups were subjected to an immediate hyperoxic condition from birth and kept at 85% O2 levels for 14 days followed by a 14-day period in room air. Next, mice lung tissue was used for RNA and DNA extraction with subsequent microarray-based assessment of lung transcriptome and supplementary methylome analysis.

Results: The immune system-related transcriptomeregulation was affected in mouse lungs after hyperoxia. A high proportion of genes relevant in the immune system exhibited significant expression alterations, e.g., B cell-specific genes central to the cytokine-cytokine receptor interaction, the PI3K-AKT, and the B cell receptor signaling pathways. The findings were accompanied by significant DNA hypermethylation observed in the PI3K-AKT pathway and immune system-relevant genes.

Conclusions: Oxygen damage could be partly responsible for the increased susceptibility and abnormal response to respiratory viruses and infections seen in premature babies with BPD through dysregulated genes.
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http://dx.doi.org/10.1159/000501461DOI Listing
June 2020

Pulmonary vascular disease is evident in gene regulation of experimental bronchopulmonary dysplasia.

J Matern Fetal Neonatal Med 2020 Jun 4;33(12):2122-2130. Epub 2019 Jan 4.

Department of Pediatric Research, University of Oslo, Oslo, Norway.

To examine the gene expression regarding pulmonary vascular disease in experimental bronchopulmonary dysplasia in young mice. Premature delivery puts babies at risk of severe complications. Bronchopulmonary dysplasia (BPD) is a common complication of premature birth leading to lifelong affection of pulmonary function. BPD is recognized as a disease of arrested alveolar development. The disease process is not fully described and no complete cure or prevention is known. The focus of interest in the search for treatment and prevention of BPD has traditionally been at airspace level; however, the pulmonary vasculature is increasingly acknowledged in the pathology of BPD. The aim of the investigation was to study the gene expression in lungs with BPD with regards to pulmonary vascular disease (PVD). We employed a murine model of hyperoxia-induced BPD and gene expression microarray technique to determine the mRNA expression in lung tissue from young mice. We combined gene expression pathway analysis and analyzed the biological function of multiple single gene transcripts from lung homogenate to study the PVD relevant gene expression. There were  = 117 significantly differentially regulated genes related to PVD through down-regulation of contractile elements, up- and down-regulation of factors involved in vascular tone and tissue-specific genes. Several genes also allowed for pinpointing gene expression differences to the pulmonary vasculature. The gene coding for a natriuretic peptide, a potent vasodilator, was significantly down-regulated and there was a significant up-regulation of (phosphodiesterase 1A), (prostaglandin e receptor 3), and (prostaglandin-endoperoxide synthase one). The pulmonary vasculature is affected by the arrest of secondary alveolarization as seen by differentially regulated genes involved in vascular tone and pulmonary vasculature suggesting BPD is not purely an airspace disease. Clues to prevention and treatment may lie in the pulmonary vascular system.
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http://dx.doi.org/10.1080/14767058.2018.1541081DOI Listing
June 2020

Mutations in the COL1A1 and COL1A2 genes associated with osteogenesis imperfecta (OI) types I or III.

Acta Biochim Pol 2018 15;65(1):79-86. Epub 2018 Mar 15.

Department of Pediatric Propedeutics and Bone Metabolism Diseases, Medical University in Lodz, Poland.

Although over 85% of osteogenesis imperfecta (OI) cases are associated with mutations in the procollagen type I genes (COL1A1 or COL1A2), no hot spots for the mutations were associated with particular clinical phenotypes. Eight patients that were studied here, diagnosed with OI by clinical standards, are from the Polish population with no ethnic background indicated. Previously unpublished mutations were found in six out of those eight patients. Genotypes for polymorphisms (Sp1 - rs1800012 and PvuII - rs412777), linked to bone formation and metabolism were determined. Mutations were found in exons 2, 22, 50 and in introns 13 and 51 of the COL1A1 gene. In COL1A2, one mutation was identified in exon 22. Deletion type mutations in COL1A1 that resulted in OI type I had no effect on collagen type I secretion, nor on its intracellular accumulation. Also, a single base substitution in I13 (c.904-9 G>T) was associated with the OI type I. The OI type III was associated with a single base change in I51 of COL1A1, possibly causing an exon skipping. Also, a missense mutation in COL1A2 changing Gly→Cys in the central part of the triple helical domain of the collagen type I molecule caused OI type III. It affected secretion of the heterotrimeric form of procollagen type I. However, no intracellular accumulation of procollagen chains could be detected. Mutation in COL1A2 affected its incorporation into procollagen type I. The results obtained shall help in genetic counseling of OI patients and provide a rational support for making informed, life important decisions by them and their families.
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http://dx.doi.org/10.18388/abp.2017_1612DOI Listing
October 2018

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

Ginekol Pol 2017 ;88(8):434-441

Katedra Pediatrii Klinika Chorób Dzieci Uniwerystet Jagielloński Collegium Medicum, Poland.

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.
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http://dx.doi.org/10.5603/GP.a2017.0080DOI Listing
July 2018

Genetic Background of Immune Complications after Allogeneic Hematopoietic Stem Cell Transplantation in Children.

Stem Cells Int 2016 6;2016:2626081. Epub 2016 Jan 6.

Department of Clinical Immunology, Chair of Clinical Immunology and Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka Street 265, 30-663 Krakow, Poland.

Immune reactions are among the most serious complications observed after hematopoietic stem cell transplantation (HSCT) in children. Microarray technique allows for simultaneous assessment of expression of nearly all human genes. The objective of the study was to compare the whole genome expression in children before and after HSCT. A total of 33 children referred for HSCT were enrolled in the study. In 70% of the patients HSCT was performed for the treatment of neoplasms. Blood samples were obtained before HSCT and six months after the procedure. Subsequently, the whole genome expression was assessed in leukocytes using GeneChip Human Gene 1.0 ST microarray. The analysis of genomic profiles before and after HSCT revealed altered expression of 124 genes. Pathway enrichment analysis revealed upregulation of five pathways after HSCT: allograft rejection, graft-versus-host disease, type I diabetes mellitus, autoimmune thyroid disease, and viral myocarditis. The activation of those pathways seems to be related to immune reactions commonly observed after HSCT. Our results contribute to better understanding of the genomic background of the immunologic complications of HSCT.
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http://dx.doi.org/10.1155/2016/2626081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736776PMC
February 2016

Does aberrant architecture of nuclear LINC complex stop muscle cell development?

Clin Neuropathol 2015 May-Jun;34(3):136-40

The linker of nucleoskeleton and cytoskeleton (LINC) complex is a structure that spans the entire nuclear envelope (NE) and integrates the nuclear interior with the cytoskeleton. Lamin A/C together with nesprins that mainly reside along the inner nuclear membrane (INM) and outer nuclear membrane (ONM) are core components of the LINC complex. Integrity of this specific nuclear structure is critical for muscle cell maturation and function. In the present study, we analyzed the ultrastructure of the LINC complex observed in two neonates with severe hypotonia and respiratory distress. Disruption of the LINC complex manifests in a wide separation of the ONM from the INM; the loss of perinuclear space (PNS) and delayed muscle cell maturation were predominating findings. This nuclear phenomenon has never been reported and provides further support for the appearance of a neonatal form of laminopathy.
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http://dx.doi.org/10.5414/NP300825DOI Listing
August 2015

MTRNR2L12: A Candidate Blood Marker of Early Alzheimer's Disease-Like Dementia in Adults with Down Syndrome.

J Alzheimers Dis 2015 ;46(1):145-50

Department of Clinical Genetics, Medical University Bialystok, Poland.

Morphological abnormalities observed typically in the brains of adults with Down syndrome are identical with those present in patients with Alzheimer's disease. However, only some adults with Down syndrome suffer from early dementia, whereas others remain unaffected. We aimed to identify the genomic background responsible for this observation. We performed cognitive assessment and genome expression analysis of blood mononuclear cells in seniors with Down syndrome. Unaffected elderly patients and younger patients with severe cognitive disability or cognitive deterioration differed significantly with regard to the MTRNR2L12 gene. Our findings suggest the potential value of this gene as a blood marker of early dementia in individuals with Down syndrome.
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http://dx.doi.org/10.3233/JAD-143030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878308PMC
June 2016

Identification of deletions in children with congenital hypothyroidism and thyroid dysgenesis with the use of multiplex ligation-dependent probe amplification.

J Pediatr Endocrinol Metab 2015 Jan;28(1-2):171-6

Introduction: Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism (CH). Important genetic factors possibly contributing to TD etiologies include mutations of thyroid transcription factors and TSHR-encoding genes.

Objective: Our objective was to determine multiplex ligation-dependent probe amplification (MLPA) utility in detecting the copy number changes in patients with CH and TD.

Methods: The study included 45 children from southeastern Poland selected via already established neonatal screening for CH. Genomic DNA was extracted from peripheral blood samples and used in MLPA analysis. Genetic variations were analyzed within selected fragments of the PAX8, FOXE1, NKX2-1, thyroid stimulating hormone receptor (TSHR), and TPO genes.

Results: Three heterozygous deletion types in probe hybridization regions were identified for the following genes: PAX8 (exon 7), TSHR (exon 2), and FOXE1 (exon 1). Monoallelic deletions were identified in 5/45 TD subjects.

Conclusions: MLPA is a useful tool for copy number changes detection and might both improve and expand genetic analysis for CH and TD.
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http://dx.doi.org/10.1515/jpem-2014-0040DOI Listing
January 2015

Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine manufactured with and without polysorbate 80 given to healthy infants at 2, 3, 4 and 12 months of age.

Pediatr Infect Dis J 2015 Feb;34(2):180-5

From the *Department of Neonatology, Poznań University of Medical Sciences, Poznan, Poland; †Pfizer Vaccine Research, Maidenhead, United Kingdom; ‡Department of Preventive Medicine, Poznań University of Medical Sciences, Poznan; §Physicians Practice Group Family Specialist Outpatient Clinic, Torun; ¶The Wl. Bieganski Provincial Specialist Hospital of Lodz, Lodz; ‖The St. Luis Provincial Specialist Children's Hospital, Cracow; **The Dr. Biziel University Hospital No. 2 of Bydgoszcz, Bydgoszcz; ††University Children's Hospital of Cracow, Cracow; ‡‡Vaccine Research, Pfizer Inc, Pearl River, NY; and §§Pfizer Vaccines Research, Pfizer Inc, Collegeville, PA.

Background: Polysorbate 80 (P80), a nonionic detergent used to solubilize proteins, is used in both oral and injectable medications including vaccines. Development studies with 13-valent pneumococcal conjugate vaccine (PCV13) showed that adding P80 resulted in a more robust manufacturing process. Before adding P80 to the formulation of PCV13, we investigated the immunogenicity and safety of PCV13 with and without P80.

Methods: Phase 3, parallel-group, randomized, active-controlled, double-blind multicenter trial was conducted at 15 sites in Poland. Healthy infants were randomized (1:1) to receive PCV13+P80 or PCV13 without P80 given at ages 2, 3, 4 and 12 months concomitantly with DTaP-IPV-Hib at 2, 3 and 4 months; hepatitis B at 2 months and measles, mumps, and rubella at 12 months. Serotype-specific antipneumococcal immune responses were evaluated using antipolysaccharide capsular immunoglobulin (Ig)G responses and opsonophagocytic activity (OPA) assay. Safety data were also collected.

Results: The 2 treatment groups were demographically similar. Following the infant immunization series, anticapsular IgG antibody geometric mean concentrations and OPA geometric mean titers for each serotype were within 2-fold between the 2 groups. Formal noninferiority criteria for comparison of proportion of responders (subjects with IgG titers ≥0.35 μg/mL) were met for 11 of the 13 serotypes. Overall population responses were highly similar. Anticapsular IgG responses were also within 2-fold following the toddler dose. Safety profiles were similar between the 2 groups.

Conclusions: Addition of P80 to PCV13 did not adversely affect PCV13 immunogenicity or safety when compared with vaccine formulated without P80.
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http://dx.doi.org/10.1097/INF.0000000000000511DOI Listing
February 2015

Impact of Hymenoptera venom allergy and the effects of specific venom immunotherapy on mast cell metabolites in sensitized children.

Ann Agric Environ Med 2014 ;21(2):294-301

Chair of Pediatrics, Department of Pediatrics, Jagiellonian University Medical College, Cracow, Poland.

Introduction And Objective: Mast cells (MC) are effector cells during severe systemic reactions (SR) to Hymenoptera stings. Venom specific immunotherapy (VIT) is the treatment of choice for prevention of SR to stings. Tryptase and prostaglandin D₂ metabolites (PGD₂) are the markers of MC activation. The study design was to 1. compare baseline values of serum tryptase concentration (BST) and PGD₂ metabolites in children with/without venom sensitization, 2. to evaluate an influence of rush VIT on MC markers in treated children.

Materials And Methods: Sensitized group: 25 children with SR to Hymenoptera sting.

Control Group: 19 healthy children. Active treatment: 5-day-rush-VIT. BST was evaluated by ImmunoCAP, PGD₂ metabolites in blood and urine by GC-NICI-MS.

Results: The baseline blood levels of MC markers were significantly higher, while urinary concentration of 9α,11β-PGF₂ was significantly lower in the whole group of venom-sensitized children compared to controls. Severity of SR showed negative correlation with urinary PGD₂ metabolites, while positive with plasma 9α,11β-PGF₂ and BST concentration The highest sensitivity was obtained for plasma 9α,11β-PGF₂ whereas the highest specificity for urinary PGD-M.

Conclusions: In children with IgE-mediated SR to Hymenoptera stings, elevation of baseline values of PGD₂ metabolites in blood is accompanied by decreased excretion of its urinary metabolites. Assessment of stable PGD₂ metabolites might serve as an independent MC marker to identify allergic children. There is an association between urinary PGD₂ metabolites and severity of the SR to Hymenoptera stings.
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http://dx.doi.org/10.5604/1232-1966.1108594DOI Listing
February 2015

Hypoxia-reoxygenation affects whole-genome expression in the newborn eye.

Invest Ophthalmol Vis Sci 2014 Mar 10;55(3):1393-401. Epub 2014 Mar 10.

Department of Pediatric Research, Clinic of Women and Child Health, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.

Purpose: Resuscitation of newborns is one of the most frequent procedures in neonatal medicine. The use of supplementary oxygen during resuscitation of the asphyxiated newborn has been shown to be detrimental to vulnerable tissues. We wanted to assess transcriptional changes in ocular tissue after the acute use of oxygen in the delivery room in a hypoxia-reoxygenation model of the newborn mouse.

Methods: C57BL/6 mice (n = 57), postnatal day 7, were randomized to receive either 120 minutes of hypoxia, at 8% O2, followed by 30 minutes of reoxygenation with 21, 40, 60, or 100% O2 or to normoxia followed by 30 minutes of 21% or 100% O2. Whole ocular homogenates were analyzed by Affymetrix 750k expression array, and RT-PCR was performed for validation. Bayesian analysis of variance for microarray data (BAMarray) was used to identify single significant genes, and Gene Set Enrichment Analysis (GSEA) was applied to reveal significant pathway systems.

Results: In total, ∼ 92% of the gene expression changes were altered in response to reoxygenation with 60% or 100% O2 compared to expression at the lower percentages of 21% and 40%. After 100% O2 treatment, genes involved in inflammation (Ccl12), angiogenesis (Igfr1, Stat3), and metabolism (Hk2) were upregulated. Pathway analyses after hypoxia-reoxygenation revealed significant alterations of six pathways which included apoptosis, TGF-beta signaling, oxidative phosphorylation, voltage-gated calcium channel complex, mitochondrion, and regulation of RAS protein signal transduction.

Conclusions: Hypoxia-reoxygenation can induce immediate transcriptional responses in ocular tissue involving inflammation, angiogenesis, energy failure, and Ras signaling.
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http://dx.doi.org/10.1167/iovs.13-13159DOI Listing
March 2014

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

Pediatr Res 2014 Apr 27;75(4):517-26. Epub 2013 Dec 27.

Department of Pediatric Research, Clinic of Women and Child Health, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.

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.
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http://dx.doi.org/10.1038/pr.2013.249DOI Listing
April 2014

Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.

Acta Biochim Pol 2013 17;60(4):613-6. Epub 2013 Dec 17.

Chair of Pediatrics, Jagiellonian University, Krakow, Poland.

Tetrahydrobiopterin (BH4) has been recently approved as a treatment of patients with phenylketonuria. However, as a confirmation of BH4-responsiveness, it might require a very expensive trial treatment with BH4 or prolonged BH4-loading procedures. The selection of patients eligible for BH4-therapy by means of genotyping of the PAH gene mutations may be recommended as a complementary approach. A population-wide genotyping study was carried out in 1286 Polish phenyloketonuria-patients. The aim was to estimate the BH4 demand and to cover prospectively the treatment by a National Health Fund. A total of 95 types of mutations were identified. Genetic variants corresponding with probable BH4-responsiveness were found in 28.2% of cases. However, patients with mild or classical phenylketonuria who require continuous treatment accounted for 11.4% of the studied population only. Analysis of the published data shows similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe. Therefore, it can be concluded, that the proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region.
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August 2014

Gene expression profiling in preterm infants: new aspects of bronchopulmonary dysplasia development.

PLoS One 2013 23;8(10):e78585. Epub 2013 Oct 23.

Department of Pediatrics, Jagiellonian University, Krakow, Poland.

Rationale: Bronchopulmonary dysplasia is one of the most serious complications observed in premature infants. Thanks to microarray technique, expression of nearly all human genes can be reliably evaluated.

Objective: To compare whole genome expression in the first month of life in groups of infants with and without bronchopulmonary dysplasia.

Methods: 111 newborns were included in the study. The mean birth weight was 1029 g (SD:290), and the mean gestational age was 27.8 weeks (SD:2.5). Blood samples were drawn from the study participants on the 5th, 14th and 28th day of life. The mRNA samples were evaluated for gene expression with the use of GeneChip® Human Gene 1.0 ST microarrays. The infants were divided into two groups: bronchopulmonary dysplasia (n=68) and control (n=43).

Results: Overall 2086 genes were differentially expressed on the day 5, only 324 on the day 14 and 3498 on the day 28. Based on pathway enrichment analysis we found that the cell cycle pathway was up-regulated in the bronchopulmonary dysplasia group. The activation of this pathway does not seem to be related with the maturity of the infant. Four pathways related to inflammatory response were continuously on the 5(th), 14(th) and 28(th) day of life down-regulated in the bronchopulmonary dysplasia group. However, the expression of genes depended on both factors: immaturity and disease severity. The most significantly down-regulated pathway was the T cell receptor signaling pathway.

Conclusion: The results of the whole genome expression study revealed alteration of the expression of nearly 10% of the genome in bronchopulmonary dysplasia patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078585PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806835PMC
February 2015

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

Pediatr Res 2013 Nov 2;74(5):536-44. Epub 2013 Sep 2.

Department of Pediatric Research, Women and Children's Division, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.

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.
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http://dx.doi.org/10.1038/pr.2013.140DOI Listing
November 2013

Development of children's hymenoptera venom allergy quality of life scale (CHVAQoLS).

Clin Transl Allergy 2013 Aug 1;3(1):25. Epub 2013 Aug 1.

Department of Pediatrics, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.

Background: Venom allergy is a rare but life-threatening disease and may have a considerable impact on the health-related quality of life (HRQoL) of patients, especially children. This paper presents development of the HRQoL scale for children and adolescents with Hymenoptera venom allergy (HVA).

Methods: The study sample consisted of 71 children, born between 1992 and 2000, who presented with a history of insect sting reaction when referred for consultation in the allergy center of Polish-American Children's Hospital, Krakow, Poland, during the period from 2000 to 2010. The initial pool of 60 items - divided into 6 domains - was prepared. The items with intercorrelations higher than 0.7 were removed from each domain and then principal component analysis was conducted for each domain separately, to provide a one-dimensional subscale for each domain. Reliability of the subscales was assessed using Cronbach alpha coefficient in terms of Classical Test Theory and with rho coefficient in terms of Item Response Theory. The multidimensionality of the scale was tested using multi-trait scaling.

Results: Three to four items from each domain were subsequently selected to constitute six subscales. Rho coefficients for all the subscales reached 0.8, similar results were achieved with the Cronbach alpha coefficients. Multi-trait method showed that the majority of the items indicated stronger correlations with their own subscales than with other subscales, which proves that our constructed subscales measure different dimensions of HRQoL.

Conclusions: The presented scale comprises high validity and reliability subscales measuring six dimensions of HRQoL related to Hymenoptera venom allergy in children and adolescents. Such information may be useful in everyday clinical practice.
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http://dx.doi.org/10.1186/2045-7022-3-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750314PMC
August 2013

A novel conserved mutation in SGCE gene in 3 unrelated patients with classical phenotype myoclonus-dystonia syndrome.

Neurol Res 2013 Jul 14;35(6):659-62. Epub 2013 Jan 14.

Department of Medical Genetics, Jagiellonian University Medical College, Kraków, Poland.

Objective And Importance: Myoclonus-dystonia syndrome (MDS, DYT11) is an inherited disorder characterized by clinical and genetic heterogeneity. MDS is inherited in autosomal dominant pattern and caused by heterozygous mutations in the gene encoding epsilon-sarcoglycan (SGCE) on chromosome 7q21. SGCE gene mutations are present in about 30-50% patients classified as definite-MDS. Earlier onset of motor symptoms is indicated in MDS patients who are SGCE mutations carriers. We present clinical phenotype of three unrelated MDS patients bearing novel, not described yet, mutation in SGCE gene.

Clinical Presentation: Presence of a substantial mutation in exon 3, changing aspartic acid to asparagine in codon 96 (D96N) of SGCE protein has been revealed. Three unrelated individuals, bearing the same mutation have diversity of symptoms, with some common features. Age of onset of our patients differs: 2, 14 to 38 years of age. Intervention/technique: Detection of mutations in SGCE gene was performed via direct sequencing of SGCE gene.

Conclusions: Our results confirm the role of the SGCE gene in the pathogenesis of MDS and call into question the impact of SGCE mutations on the age of onset. The existing list of known mutations and diversity of symptoms in patients bearing the same mutation indicates that there is a lack of genotype-phenotype correlation. Heterogeneity of disease indicates necessity for further research in order to find the molecular fingerprint which may be a landmark in diagnostic studies of MDS.
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http://dx.doi.org/10.1179/1743132812Y.0000000146DOI Listing
July 2013

[Congenital cytomegaly in one twin - a case report].

Med Wieku Rozwoj 2012 Jul-Sep;16(3):252-60

Klinika Chorób Dzieci Katedry Pediatrii, Uniwersytet Jagielloński, Collegium Medium w Krakowie, ul. Wielicka 265, 30-663 Kraków.

A report on dichorionic/diamniotic pregnancy in which only one, female, fetus was infected with cytomegalovirus and presented with severe congenital diseases at birth. Infection of the fetus occurred after recurrent maternal infection. The second, male, fetus did not have CMV infection. The cesarean section was performed at the 38th week of gestation. The birth weight of the infected girl was 1680g, the main symptoms, beside dystrophy, concerned the central nervous system: microcephaly, brain atrophy, hydrocephalus, corpus callosum agenesis. She also had Turner syndrome symptoms. The viral load was highest in the urine 81.2 x10^6/ml, in the cerebro-spinal fluid 15.4x10^6/ml and lower in blood 0.38 x10^5/ml. The concentration of specific IgG was 308 U/ml. Specific IgM was not detected. Throughout hospitalization, the infection maintained only one viral genotype gB2. Despite treatment with ganciclovir (10 weeks) and foscarnet (2 weeks), the girl died at the age of 8 months. Novel molecular diagnostic techniques (nested and real time PCR) confirmed the congenital infection and were helpful in the monitoring of the infection and treatment efficacy.
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April 2013

Assessment of the role of copy-number variants in 150 patients with congenital heart defects.

Med Wieku Rozwoj 2012 Jul-Sep;16(3):175-82

Department of Medical Genetics, Institute of Mother and Child, ul. Kasprzaka 17a, 01-211, Warsaw.

Background: Congenital heart defects are the most common group of major birth anomalies and one of the leading causes of infant deaths. Mendelian and chromosomal syndromes account for about 20% of congenital heart defects and in some cases are associated with other malformations, intellectual disability, and/or dysmorphic features. The remarkable conservation of genetic pathways regulating heart development in animals suggests that genetic factors can be responsible for a significantly higher percentage of cases.

The Aim: Assessment of the role of CNVs in the etiology of congenital heart defects using microarray studies.

Material And Methods: Genome-wide array comparative genomic hybridization, targeting genes known to play an important role in heart development or responsible for abnormal cardiac phenotype was used in the study on 150 patients. In addition, we have used multiplex ligation-dependent probe amplification specific for chromosome 22q11.2 region.

Results: We have identified 21 copy-number variants, including 13 known causative recurrent rearrangements (12 deletions 22q11.2 and one deletion 7q11.23), three potentially pathogenic duplications (5q14.2, 15q13.3, and 22q11.2), and five variants likely benign for cardiac anomalies. We suggest that abnormal copy-number of the ARRDC3 and KLF13 genes can be responsible for heart defects.

Conclusions: Our study demonstrates that array comparative genomic hybridization enables detection of clinically significant chromosomal imbalances in patients with congenital heart defects.
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April 2013

Health-related quality of life in Polish adolescents with Hymenoptera venom allergy treated with venom immunotherapy.

Arch Med Sci 2012 Dec 19;8(6):1076-82. Epub 2012 Dec 19.

Chair of Pediatrics, Department of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.

Introduction: Venom allergy, though rare, may seriously influence health-related quality of life (HRQoL). There is a paucity of research on HRQoL of adolescents and young adults with Hymenoptera venom allergy. The aim was to assess the level of HRQoL and to evaluate its independent predictors in Polish adolescents and young adults treated with venom immunotherapy.

Material And Methods: A multicenter cross-sectional study based on the Vespid Allergy Quality of Life Questionnaire (VQLQ) adapted for Polish adolescents was used. The study sample included 87 patients (14-21 years) studied at different stages of venom immunotherapy (VIT). Statistical analysis was done with multivariate linear regression.

Results: Anxiety level was higher in patients with 4(th) grade of Mueller's classification (anaphylactic shock) than in those with 3(rd) grade (B = 0.84, 95% CI = 0.07-1.61, p = 0.03). Caution increased along with an increase of anxiety of adolescents treated with VIT (B = 0.54, 95% CI = 0.39-0.68, p < 0.01). Level of limitations increased with increasing caution of adolescents (B = 0.63, 95% CI = 0.35-0.91, p < 0.01). Discomfort increased along with a rise of caution of patients (B = 0.38, 95% CI = 0.22-0.55, p < 0.01). Similarly, it increased with an increase of their feeling of limitations (B = 0.37, 95% CI = 0.23-0.51, p < 0.01). The level of discomfort in adolescents treated with VIT was lower in those who were treated with conventional protocol in comparison to those treated with rush or ultra-rush ones (B = -0.47, 95% CI = -0.90 - -0.03, p = 0.04).

Conclusions: Severity of anaphylactic reaction is an independent determinant of anxiety level in adolescents treated with VIT. The VIT protocol affects HRQoL of treated patients.
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http://dx.doi.org/10.5114/aoms.2012.32419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542499PMC
December 2012

Coronary artery abnormalities in Kawasaki disease.

Folia Med Cracov 2013 ;53(1):13-21

Department of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.

Introduction: Kawasaki disease is the number one cause of acquired heart disease among children in developed countries.

Aim: The aim of the study was a retrospective analysis of the factors that may influence the persistence of coronary artery abnormalities in patients with Kawasaki disease.

Materials And Methods: Analyzing the medical records of patients hospitalized in the University Children's Hospital of Krakow in the years 2005-2011 we collected the data of 28 patients diagnosed with Kawasaki disease. The group was divided into two subgroups, depending on the duration of the persistence of changes in the coronary arteries - A (n = 17) for up to 6 months, B (n = 11) - for more than 6 months. Both groups were analyzed for the presence of factors that may influence the course of the disease.

Results: There were more boys in group A (11 boys (65%), 6 girls (35%)), whereas in group B the distribution was more uniform (6 boys (55%), 5 girls (45%)). The age of onset in group A was 37.9 months (SD 30.8), in group B 39.5 months (SD 16.7). 17.6% of patients in group A and 36.4% in group B were treated with glucocorticoids.

Conclusions: In the group of patients in which coronary artery abnormalities disappeared more quickly, male and slightly older children dominated. The only difference observed between the 2 groups related to the frequency of the use of glucocorticoids, they were used more often in children, in whom coronary artery abnormalities persisted longer.
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July 2014

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

Pediatr Res 2013 Apr 26;73(4 Pt 1):476-83. Epub 2012 Dec 26.

Department of Pediatrics, Jagiellonian University, Krakow, Poland.

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.
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http://dx.doi.org/10.1038/pr.2012.195DOI Listing
April 2013

Congruence of the current practices in Hymenoptera venom allergic patients in Poland with EAACI guidelines.

Arch Med Sci 2011 Oct 8;7(5):832-9. Epub 2011 Nov 8.

Department of Pediatrics, Polish-American Children's Hospital, Jagiellonian University Medical College, Krakow, Poland.

Introduction: Venom immunotherapy (VIT) practice is the definitive treatment for patients with potentially fatal allergic reactions to Hymenoptera stings. The aim is assesing compliance of VIT practice in Poland with the current European Academy of Allergy and Clinical Immunology (EAACI) guidance.

Material And Methods: A multicentre study was carried out using a structured questionnaire which was sent by post to all VIT practitioners in Poland. Some questionnaire items were altered, in comparison to original version by adding additional answer options or alowing multiple answer option. The response rate was 100%. The obtained results were compared with the published EAACI guidelines.

Results: Twenty-six Polish centres took part in the survey. SSIgE and skin prick tests (SPT) are together used as the first line of investigation, whereas confirmatory intradermal tests (IDT) are applied in half of centres. Only a few centres measure baseline serum tryptase levels. The ultra-rush protocol is preferred. Antihistamine pre-medication is routinely practiced. A target dose equal to 100 µg is used in most centres. A 6-week interval between booster doses is the most frequent. Five years is considered as an optimal VIT duration. Before the VIT completion, SSIgE is evaluated in fifty percent of centres, whereas sting challenge is considered by half of responders.

Conclusions: There are some differences between current practice in Poland and the EAACI recommendations, indicating areas requiring better compliance. Comparision between Poland and the United Kingdom revealed that health service organization and health care funding may play a major role in the provision of allergy services. This may affect the extent to which international guidance may be applied in individual countries. It is worth considering conducting the same survey in other European countries.
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http://dx.doi.org/10.5114/aoms.2011.25558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258816PMC
October 2011

Laboratory markers of mast cell and basophil activation in monitoring rush immunotherapy in bee venom-allergic children.

Immunotherapy 2011 Aug;3(8):1013-7

Department of Pediatrics, Polish-American Children's Hospital, Medical Faculty, Jagiellonian University Medical College, Krakow, Poland.

Aim: To evaluate markers of mast cell and basophil activation in children undergoing the initial phase of honeybee venom immunotherapy (VIT).

Patients & Methods: Five children (four boys and one girl) aged 9.5-18 years with severe systemic bee sting reactions and confirmed IgE-mediated allergy were enrolled. Plasma and urine concentrations of 9α,11β-PGF2 and serum tryptase levels were measured at four time points and peripheral blood basophil count and CD63 expression were measured at three time points in the course of VIT, including 5-day rush initial immunotherapy (cumulative dose of 223 µg of bee venom allergen) and two subsequent maintenance doses of 100 µg.

Results: In the first 40 days of VIT, there was a decrease in mean plasma levels of 9α,11β-PGF2 (from 41.5 to 27.9 pg/ml; p < 0.05), accompanied by an increase in baseline basophil activation (from 2 to 15%; p < 0.05). The median serum tryptase levels increased from 3.45 to 4.40 ng/ml during rush phase and subsequently returned to initial values (statistically not significant). In four patients, the basophil activation test in response to bee venom allergens remained positive throughout the study. The fifth patient was basophil activation test-negative at all three measurements, and a post hoc analysis revealed clinical peculiarities that are discussed in the paper.

Conclusions: Our preliminary results indicate that plasma levels of 9α,11β-PGF2 decrease while numbers of activated basophils increase during the initial phase of bee venom rush immunotherapy in children.
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http://dx.doi.org/10.2217/imt.11.91DOI Listing
August 2011

[Use of computerized neuropsychological tests and of nuclear magnetic resonance spectroscopy in clinical assessment of adult patients with phenylketonuria].

Przegl Lek 2011 ;68(3):127-31

Zakład Genetyki Medycznej Katedry Pediatrii, Uniwersytetu Jagiellońskiego, Collegium Medicum, Kraków.

Phenylketonuria is the most common inborn error of metabolism. Adult patients often discontinue dietary treatment and can subsequently develop serious brain dysfunction. Some of them, however, do not present any symptoms, despite long-term exposition to high blood phenylalanine concentration. As the extent of brain toxicity of hyperphenylalaninemia is not clear in adults, new diagnostic methods are needed to assess brain effects of hyperphenylalaninemia. The aim of the study was to evaluate the usefulness of magnetic resonance spectroscopy and of computerized neuropsychological tests for measurement of brain phenylalanine concentration and for early detection of hyperphenylalaninemia-related brain dysfunction. Assessment of sustained attention, working memory and inhibitive control was performed in a group of 50 adults with phenylketonuria by means of computerized CANTAB system. Additionally, in 40 patients, measurement of brain phenylalanine signal was done by means of magnetic resonance spectroscopy. The results were correlated with plasma phenylalanine concentrations. Worsening of neuropsychological efficiency as well as increase of brain phenylalanine concentration correlated with high levels of plasma phenylalanine. Interestingly, in two cases, despite high plasma phenylalanine concentration, low brain phenylalanine concentration was observed accompanied by good results of neuropsychological tests. This finding suggests presence of mechanisms limiting brain toxicity of hyperphenylalaninemia in some patients. It should be stressed, however, that such situation can be expected rarely, and is probably restricted to cases with moderate hyperphenylalaninemia. Combination of computerized neu- ropsychological tests and of magnetic resonance spectroscopy is a useful diagnostic method which could allow for careful individualization of dietary recommendations in selected patients with phenylketonuria.
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December 2011

Plasma levels of leptin and soluble leptin receptor and polymorphisms of leptin gene -18G > A and leptin receptor genes K109R and Q223R, in survivors of childhood acute lymphoblastic leukemia.

J Exp Clin Cancer Res 2011 Jun 1;30:64. Epub 2011 Jun 1.

Department of Immunology, Chair of Clinical Immunology and Transplantation, Jagiellonian University Medical College, ul. Wielicka 265, Krakow, Poland.

Background: Approximately 20% of children and adolescents in Europe are overweight. Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of overweight and obesity. The purpose of this study was to assess leptin and leptin soluble receptor levels, as well as polymorphisms of selected genes in survivors of pediatric ALL, and the influence of chemo- and radiotherapy on development of overweight in the context of leptin regulation.

Methods: Eighty two patients (55% males), of median age 13.2 years (m: 4.8 years; M: 26.2 years) were included in the study. The ALL therapy was conducted according to modified Berlin-Frankfurt-Munster (BFM; n = 69) regimen or New York (n = 13) regimen. In 38% of patients cranial radiotherapy (CRT) was used in median dose of 18.2Gy (m: 14Gy; M: 24Gy). Median age at diagnosis was 4.5 (m: 1 year; M: 16.9 years) and median time from completion of ALL treatment was 3.2 years (m: 0.5 year; M: 4.3 years). Patients with BMI ≥85 percentile were classified as overweight. Correlation of plasma levels of leptin and leptin soluble receptor, and polymorphisms of leptin gene -18G > A, leptin receptor genes K109R and Q223R, and the overweight status were analyzed in relation to gender, intensity of chemotherapy (high intensity vs. standard intensity regimens) and to the use of CRT.

Results: Significant differences of leptin levels in patients treated with and without CRT, both in the entire study group (22.2+/- 3.13 ng/ml vs. 14.9+/-1.6 ng/ml; p < 0.03) and in female patients (29.9+/-4.86 ng/ml vs. 16.9+/-2.44 ng/ml; p = 0.014), were found. Significant increase of leptin levels was also found in overweight patients compared to the non-overweight patients in the entire study group (29.2+/-2.86 ng/ml vs. 12.6+/-1.51 ng/ml; p < 0.0001), female patients (35.4+/-6.48 ng/ml vs. 18.4+/-2.5 ng/ml; p = 0.005), and male patients (25.7+/-2.37 ng/ml vs. 6.9+/-0.95 ng/ml; p < 0.0001). Negative correlation was observed for plasma levels of soluble leptin receptor and overweight status, with significant differences in overweight and non-overweight patients, both in the entire study group (18.2+/-0.75 ng/ml vs. 20.98+/-0.67 ng/ml; p = 0.017) and in male patients (18.2+/-1.03 ng/ml vs. 21.8+/- 1.11 ng/ml; p = 0.038). Significant (p < 0.05) negative correlation was found between leptin and leptin receptor levels in the entire group (correlation coefficient: 0.393) and in both gender subgroups (correlation coefficient in female patients: -0.427; in male patients: -0.396).

Conclusions: The prevalence of overweight in our cohort was higher than in general European population (31% vs 20%) and increased regardless of the use of CRT. Leptin and leptin receptor levels may be used as useful markers of high risk of becoming overweight in ALL survivors, particularly in females treated with CRT. Polymorphisms of leptin gene -18G > A and leptin receptor genes K109R and Q223R were not associated with overweight status in ALL survivors.
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http://dx.doi.org/10.1186/1756-9966-30-64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127776PMC
June 2011

Blood phenylalanine clearance and BH(4)-responsiveness in classic phenylketonuria.

Mol Genet Metab 2011 Aug 1;103(4):399-400. Epub 2011 May 1.

Department of Medical Genetics, Jagiellonian University, Poland.

Tetrahydrobiopterin (BH(4)) has been shown to decrease blood phenylalanine concentration in selected patients with phenylketonuria who can be identified with use of the BH(4)-loading test. However, the results of the test could be biased due to hydroxylation-independent blood phenylalanine clearance. Considering of this effect is necessary in patients with classic phenylketonuria, particularly in "slow responders," in whom borderline decrease in blood phenylalanine concentration is typically observed as a result of BH(4)-loading.
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http://dx.doi.org/10.1016/j.ymgme.2011.04.014DOI Listing
August 2011

[Do infants treated in the neonatal intensive care unit need multi-stage, universal hearing screening testing?].

Przegl Lek 2011 ;68(1):47-53

Klinika Chorób Dzieci, Uniwersytecki Szpital Dzieciecy w Krakowie.

Introduction: The universal hearing screening program has special value for neonatal intensive care unit (NICU) patients because of the multiple risk factors of hearing loss they are subjected to.

Aim: To summarize the results of hearing tests on consecutive stages of the screening program and to evaluate the value of hearing loss factors.

Materials And Methods: The group included 851 infants born between 1.10.2006 - 31.12.2009 and treated in the NICU of the University Children's Hospital in Cracow, Poland. Infants with abnormal screening test results (TEOAE) and/or with hearing loss risk factors, or absent from the first stage of the test were qualified for the next stage hearing diagnostics (TEOAE+ABR). Multivariate logistic regression was used in order to evaluate hearing loss risk factors.

Results: 679 (80%) newborns were screened by the first stage hearing test. 579 (68%) were tested on the second level diagnostics. 60 patients are still under control. 11/519 (2.1%) had hearing impairment (sensorineual or mixed). 10 had bilateral and 1 had unilateral hearing impairment. The family history was negative for congenital hypoacusis. 1st minute Apgar score < 4 points, congenital TORCH infections and craniofacial anomalies were independent risk factors of hearing loss, however it was not possible to predict more than 2/11 patients with hearing loss based on these factors. Patients with abnormal result of the first stage test had lower birth weight and gestation age than that with normal result. The sensitivity of the first TEOAE test was 82%, specificity 70%, PPV 6.2%, NPV 99%.

Conclusion: Hearing impairment was rarely a complication of treatment in the NICU, although it was 10 times more frequent in comparison to the whole newborn population. Because the sensitivity, specificity and PPV of first hearing test is not satisfactory, next stage diagnostics in the audiology department are strongly recommended.
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October 2011

[The use of microarrays for gene expression analysis in premature children--new strategy of searching for genetic basis of late complications of prematurity--preliminary research].

Przegl Lek 2011 ;68(1):44-6

Katedra Pediatrii CM UJ w Krakowie.

Progress achieved in the development of medical care for children born prematurely has resulted in increased survival of the smallest and most immature infants. At the same time increased incidence of the late complications of prematurity such as bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) has become a growing problem. The aim of the study was to identify groups of genes potentially involved in the development of long-term complications of prematurity, by conducting genome wide microarray expression analysis. The prospective cohort study was conducted, 52 premature babies were included. At the 5th, 14th and 28th day of life samples of the peripheral blood were taken from the study participants. Subsequently, total RNA was extracted and microarray experiment, with the use of GeneChip Human Gene 1.0 ST Array (Affymetrix), was performed. The analysis of the results was carried out in the separate cohorts of prematures. Within 52 infants 2 groups were distinguished--children without BPD (n = 25) and children with BPD (n = 27). Significant difference in the expression of 251 genes was observed. Additionally, a group of 20 participants of the study, in whom ROP was diagnosed, was compared with the group of the remaining 32 children without proven retinopathy. The analysis revealed a significant difference in the expression between the analyzed groups with regard to 752 genes. Further study is needed to verify the obtained results. The impact of the over- and underexpressed genes should be studied, as well as detailed analysis of the metabolic pathways should be performed.
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October 2011