Medicine and Health Sciences Commons^™

A Population Pharmacokinetic Model For Simvastatin And Its Metabolites In Children And Adolescents., Kayode Ogungbenro, Jonathan B. Wagner, Susan M. Abdel-Rahman, J Steven Leeder, Aleksandra Galetin

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Poor adherence to dietary/behaviour modifications as interventions for hypercholesterolemia in paediatric patients often necessitates the initiation of statin therapy. The aim of this study was to develop a joint population pharmacokinetic model for simvastatin and four metabolites in children and adolescents to investigate sources of variability in simvastatin acid exposure in this patient population, in addition to SLCO1B1 genotype status.

METHODS: Plasma concentrations of simvastatin and its four metabolites, demographic and polymorphism data for OATP1B1 and CYP3A5 were analysed utilising a population pharmacokinetic modelling approach from an existing single oral dose (10 mg < 17 years and 20 mg ≥ 18 years) pharmacokinetic dataset of 32 children and adolescents.

RESULTS: The population PK model included …

New Insights Into Dna Methylation Signatures: Smarca2 Variants In Nicolaides-Baraitser Syndrome., Eric Chater-Diehl, Resham Ejaz, Cheryl Cytrynbaum, Michelle T. Siu, Andrei Turinsky, Sanaa Choufani, Sarah J. Goodman, Omar Abdul-Rahman, Melanie Bedford, Naghmeh Dorrani, Kendra Engleman, Josue Flores-Daboub, David Genevieve, Roberto Mendoza-Londono, Wendy Meschino, Laurence Perrin, Nicole Safina, Sharron Townshend, Stephen W. Scherer, Evdokia Anagnostou, Amelie Piton, Matthew Deardorff, Michael Brudno, David Chitayat, Rosanna Weksberg

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures.

METHODS: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification …

Gnrh Agonist Improves Hyperandrogenism In An Adolescent Girl With An Insulin Receptor Gene Mutation., Emily Paprocki, Romina Barral, Heidi Vanden Brink, Marla Lujan, Tania S. Burgert

Manuscripts, Articles, Book Chapters and Other Papers

Type A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range/dL), free testosterone 2.21 ng/dL (reference rangeA(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy …

Splice-Altering Variant In Col11a1 As A Cause Of Nonsyndromic Hearing Loss Dfna37., Kevin T. Booth, James W. Askew, Zohreh Talebizadeh, Patrick L M Huygen, James Eudy, Judith Kenyon, Denise Hoover, Michael S. Hildebrand, Katherine R. Smith, Melanie Bahlo, William J. Kimberling, Richard J H Smith, Hela Azaiez, Shelley D. Smith

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family.

METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family.

RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 …

Proteomic Alterations Of Hdl In Youth With Type 1 Diabetes And Their Associations With Glycemic Control: A Case-Control Study, Evgenia Gourgari, Junfeng Ma, Martin P. Playford, Nehal N. Mehta, Radoslav Goldman, Alan T. Remaley, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.

Methods: This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and …

H3k27m Induces Defective Chromatin Spread Of Prc2-Mediated Repressive H3k27me2/Me3 And Is Essential For Glioma Tumorigenesis., Ashot S. Harutyunyan, Brian Krug, Haifen Chen, Simon Papillon-Cavanagh, Michele Zeinieh, Nicolas De Jay, Shriya Deshmukh, Carol C L Chen, Jad Belle, Leonie G. Mikael, Dylan M. Marchione, Rui Li, Hamid Nikbakht, Bo Hu, Gael Cagnone, Warren A. Cheung, Abdulshakour Mohammadnia, Denise Bechet, Damien Faury, Melissa K. Mcconechy, Manav Pathania, Siddhant U. Jain, Benjamin Ellezam, Alexander G. Weil, Alexandre Montpetit, Paolo Salomoni, Tomi Pastinen, Chao Lu, Peter W. Lewis, Benjamin A. Garcia, Claudia L. Kleinman, Nada Jabado, Jacek Majewski

Manuscripts, Articles, Book Chapters and Other Papers

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on …

Considerations For Implementing Precision Therapeutics For Children., Matthew J. Mclaughlin, Jonathan B. Wagner, Valentina Shakhnovich, Bruce Carleton, J Steven Leeder

Manuscripts, Articles, Book Chapters and Other Papers

Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contributes to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. With significant improvements in characterizing both the ontogeny and genetic contributions of drug metabolizing enzymes, the time is right to begin placing more emphasis on …

Model-Based Methods To Translate Adolescent Medicine Trials Network For Hiv/Aids Interventions Findings Into Policy Recommendations: Rationale And Protocol For A Modeling Core (Atn 161), Anne M. Neilan, Kunjal Patel, Allison L. Agwu, Ingrid V. Bassett, K. Rivet Amico, Catherine M. Crespi, Aditya H. Gaur, Keith J. Horvath, Kimberly A. Powers, H. Jonathon Rendina, Lisa B. Hightow-Weidman, Xiaoming Li, Sylvie Naar, Sharon Nachman, Jeffrey T. Parsons, Kit N. Simpson, Bonita F. Stanton, Kenneth A. Freedberg, Audrey C. Bangs, Michael G. Hudgens, Andrea L. Ciaranello

Publications and Research

BACKGROUND: The United States Centers for Disease Control and Prevention estimates that approximately 60,000 US youth are living with HIV. US youth living with HIV (YLWH) have poorer outcomes compared with adults, including lower rates of diagnosis, engagement, retention, and virologic suppression. With Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) support, new trials of youth-centered interventions to improve retention in care and medication adherence among YLWH are underway.

OBJECTIVE: This study aimed to use a computer simulation model, the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Adolescent Model, to evaluate selected ongoing and forthcoming ATN interventions to improve viral load suppression …

An Open-Label, Single-Dose Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Cinacalcet In Pediatric Subjects Aged 28 Days To < 6 Years With Chronic Kidney Disease Receiving Dialysis., Winnie Y. Sohn, Anthony A. Portale, Isidro B. Salusky, Hao Zhang, Lucy L. Yan, Bella Ertik, Shahnaz Shahinfar, Edward Lee, Bastian Dehmel, Bradley A. Warady

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Calcimimetics, shown to control biochemical parameters of secondary hyperparathyroidism (SHPT), have well-established safety and pharmacokinetic profiles in adult end-stage renal disease subjects treated with dialysis; however, such studies are limited in pediatric subjects.

METHODS: In this study, the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cinacalcet were evaluated in children with chronic kidney disease (CKD) and SHPT receiving dialysis. Twelve subjects received a single dose of cinacalcet (0.25 mg/kg) orally or by nasogastric or gastric tube. Subjects were randomized to one of two parathyroid hormone (PTH) and serum calcium sampling sequences: [(1) 2, 8, 48 h; or (2) …

Determination Of Insulin Resistance And Its Relationship With Hyperandrogenemia,Anti-Müllerian Hormone, Inhibin A, Inhibin B, And Insulin-Like Peptide-3 Levels In Adolescent Girls With Polycystic Ovary Syndrome, Ayli̇n Yeti̇m Şahi̇n, Fi̇rdevs Baş, Çağcil Yeti̇m, Ahmet Uçar, Şükran Poyrazoğlu, Rüveyde Bundak, Fatma Feyza Darendeli̇ler

Turkish Journal of Medical Sciences

Background/aim: This study aims to investigate the association between polycystic ovary syndrome (PCOS) and obesity and insulin resistance (IR) with respect to anti-Müllerian hormone (AMH), inhibin A (INH-A), inhibin B (INH-B), and insulin-like peptide 3 (INSL3) levels, all factors which may have an impact on IR.Materials and methods: In this cross sectional study, 52 adolescent girls diagnosed with PCOS[groups:nonobese (NO), n = 23; overweight/obese (OW/O), n = 29] were included. Blood samples were obtained to measure AMH, INH-B, INH-A, and INSL3 levels, together with hormonal and biochemical assessments. Oral glucose tolerance test (OGTT) was performed and the indexes of IR …

A Systematic Review Of Observational Studies, Demonstrating Smoking Among School Going Adolescents, Shafquat Rozi, Gillian Lancaster, Sadia Mahmud, Zahid Ahmad Butt, Talat Roome, Nida Zahid

Community Health Sciences

Objective: To characterize the methods of design and analysis currently adopted in survey research of school-based observational studies for smoking, and to identify the common pitfalls made by researchers.
Methods: The systematic review was conducted in 2009 and consisted of observational studies in school settings published between January 2005 and January 2009. Smoking status was the main outcome of interest. Following Cochrane style, five steps were followed: setting selection criteria for studies and conducting a literature search; review of abstracts; review of complete articles; data extraction and quality assessment of included studies; and, finally, synthesis of studies.
Results: Of the …

Genomic Prediction Of Relapse In Recipients Of Allogeneic Haematopoietic Stem Cell Transplantation., J Ritari, K Hyvärinen, S Koskela, M Itälä-Remes, R Niittyvuopio, A Nihtinen, U Salmenniemi, M Putkonen, L Volin, T Kwan, T Pastinen, J Partanen

Manuscripts, Articles, Book Chapters and Other Papers

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the …