J F Watchko

University of Pittsburgh, Pittsburgh, PA, United States

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Publications (130)483.06 Total impact

  • Mamdouha Ahdab-Barmada, Jon F Watchko
    Pediatric Neurology 12/2013; · 1.42 Impact Factor
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    Jon F Watchko, Claudio Tiribelli
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    ABSTRACT: The complex cascade of molecular and cellular events leading to bilirubin-induced neurotoxicity remains incompletely delineated. This review discusses bilirubin-induced brain damage and recent insights into its pathogenesis and prevention.
    New England Journal of Medicine 11/2013; 369(21):2021-2030. · 51.66 Impact Factor
  • M J Maisels, J F Watchko
    Journal of perinatology: official journal of the California Perinatal Association 07/2013; 33(7):579. · 1.59 Impact Factor
  • Jon F Watchko
    The Journal of pediatrics 02/2013; · 4.02 Impact Factor
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    ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy can lead to severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus in the United States. Neonatal testing for G6PD deficiency is not yet routine and the American Academy of Pediatrics recommends testing only in jaundiced newborns who are receiving phototherapy whose family history, ethnicity, or geographic origin suggest risk for the condition, or for infants whose response to phototherapy is poor. Screening tests for G6PD deficiency are available, are suitable for use in newborns and have been used in birth hospitals. However, US birth hospitals experience is limited and no national consensus has emerged regarding the need for newborn G6PD testing, its effectiveness or the best approach. Our review of current state of G6PD deficiency screening highlights research gaps and informs specific operational challenges to implement universal newborn G6PD testing concurrent to bilirubin screening in the United States.Journal of Perinatology advance online publication, 21 February 2013; doi:10.1038/jp.2013.14.
    Journal of perinatology: official journal of the California Perinatal Association 02/2013; · 1.59 Impact Factor
  • Japanese journal of radiology 02/2013; · 0.73 Impact Factor
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    ABSTRACT: Background:Hazardous levels of bilirubin produce oxidative stress in vitro and may play a role in the genesis of bilirubin-induced neurologic dysfunction (BIND). We hypothesized that the antioxidants taurourosdeoxycholic acid (TUDCA), 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), and minocycline (MNC) inhibit oxidative stress and block BIND in hyperbilirubinemic j/j Gunn rat pups that were given sulfadimethoxine to induce bilirubin encephalopathy.Methods:At peak postnatal hyperbilirubinemia, j/j Gunn rat pups were dosed with sulfadimethoxine to induce bilirubin encephalopathy. Pups were given TUDCA, PMIN, MNC, or vehicle pretreatment (15 min before sulfadimethoxine). After 24 h, BIND was scored by using a rating scale of neurobehavior and cerebellar tissue 4-hydroxynonenal and protein carbonyl dinitrophenyl content were determined. Nonjaundiced heterozygous N/j pups served as controls.Results:Administration of sulfadimethoxine induced BIND and lipid peroxidation but not protein oxidation in hyperbilirubinemic j/j pups. TUDCA, PMIN, and MNC each reduced lipid peroxidation to basal levels observed in nonjaundiced N/j controls, but only MNC prevented BIND.Conclusion:These findings show that lipid peroxidation inhibition alone is not sufficient to prevent BIND. We speculate that the neuroprotective efficacy of MNC against BIND involves action(s) independent of, or in addition to, its antioxidant effects.Pediatric Research (2012); doi:10.1038/pr.2012.111.
    Pediatric Research 08/2012; · 2.67 Impact Factor
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    ABSTRACT: We provide an approach to the use of phototherapy and exchange transfusion in the management of hyperbilirubinemia in preterm infants of <35 weeks of gestation. Because there are limited data for evidence-based recommendations, these recommendations are, of necessity, consensus-based. The recommended treatment levels are based on operational thresholds for bilirubin levels and represent those levels beyond which it is assumed that treatment will likely do more good than harm. Long-term follow-up of a large population will be needed to evaluate whether or not these recommendations should be modified.
    Journal of perinatology: official journal of the California Perinatal Association 06/2012; 32(9):660-4. · 1.59 Impact Factor
  • Jon F Watchko
    The Journal of pediatrics 05/2012; 161(2):179-80. · 4.02 Impact Factor
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    ABSTRACT: Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor (NF)-κB signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-κB may inhibit gene transfer by promoting inflammation in response to the transgene or vector. Therefore, we hypothesized that inhibition of pathological NF-κB activation in muscle would complement the therapeutic benefits of dystrophin gene transfer in the mdx mouse model of DMD. Systemic gene transfer using serotype 9 adeno-associated viral (AAV9) vectors is promising for treatment of preclinical models of DMD because of vector tropism to cardiac and skeletal muscle. In quadriceps of C57BL/10ScSn-Dmd(mdx)/J (mdx) mice, the addition of octalysine (8K)-NF-κB essential modulator (NEMO)-binding domain (8K-NBD) peptide treatment to AAV9 minidystrophin gene delivery resulted in increased levels of recombinant dystrophin expression suggesting that 8K-NBD treatment promoted an environment in muscle tissue conducive to higher levels of expression. Indices of necrosis and regeneration were diminished with AAV9 gene delivery alone and to a greater degree with the addition of 8K-NBD treatment. In diaphragm muscle, high-level transgene expression was achieved with AAV9 minidystoophin gene delivery alone; therefore, improvements in histological and physiological indices were comparable in the two treatment groups. The data support benefit from 8K-NBD treatment to complement gene transfer therapy for DMD in muscle tissue that receives incomplete levels of transduction by gene transfer, which may be highly significant for clinical applications of muscle gene delivery.
    Molecular Medicine 01/2012; 18(1):466-76. · 4.47 Impact Factor
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    ABSTRACT: The activation of nuclear factor κB (NF-κB) contributes to muscle degeneration that results from dystrophin deficiency in human Duchenne muscular dystrophy (DMD) and in the mdx mouse. In dystrophic muscle, NF-κB participates in inflammation and failure of muscle regeneration. Peptides containing the NF-κB Essential Modulator (NEMO) binding domain (NBD) disrupt the IκB kinase complex, thus blocking NF-κB activation. The NBD peptide, which is linked to a protein transduction domain to achieve in vivo peptide delivery to muscle tissue, was systemically delivered to mdx mice for 4 or 7 weeks to study NF-κB activation, histological changes in hind limb and diaphragm muscle and ex vivo function of diaphragm muscle. Decreased NF-κB activation, decreased necrosis and increased regeneration were observed in hind limb and diaphragm muscle in mdx mice treated systemically with NBD peptide, as compared to control mdx mice. NBD peptide treatment resulted in improved generation of specific force and greater resistance to lengthening activations in diaphragm muscle ex vivo. Together these data support the potential of NBD peptides for the treatment of DMD by modulating dystrophic pathways in muscle that are downstream of dystrophin deficiency.
    Neurobiology of Disease 05/2011; 43(3):598-608. · 5.62 Impact Factor
  • Clinica chimica acta; international journal of clinical chemistry 03/2011; 412(13-14):1275; author reply 1276. · 2.54 Impact Factor
  • Jon F Watchko
    Pediatric Critical Care Medicine 01/2011; 12(1):110-1. · 2.35 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is a devastating primary muscle disease with pathological changes in skeletal muscle that are ongoing at the time of birth. Progressive deterioration in striated muscle function in affected individuals ultimately results in early death due to cardio-pulmonary failure. As affected individuals can be identified before birth by prenatal genetic testing for DMD, gene replacement treatment can be started in utero. This approach offers the possibility of preventing pathological changes in muscle that begin early in life. To test in utero gene transfer in the mdx mouse model of DMD, a minidystrophin gene driven by the human cytomegalovirus promoter was delivered systemically by an intraperitoneal injection to the fetus at embryonic day 16. Treated mdx mice studied at 9 weeks after birth showed widespread expression of recombinant dystrophin in skeletal muscle, restoration of the dystrophin-associated glycoprotein complex in dystrophin-expressing muscle fibers, improved muscle pathology, and functional benefit to the transduced diaphragm compared with untreated littermate controls. These results support the potential of the AAV8 vector to efficiently cross the blood vessel barrier to achieve systemic gene transfer to skeletal muscle in utero in a mouse model of muscular dystrophy, to significantly improve the dystrophic phenotype and to ameliorate the processes that lead to exhaustion of the skeletal muscle regenerative capacity.
    Gene therapy 11/2010; 17(11):1355-62. · 4.75 Impact Factor
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    Jon F Watchko, M Jeffrey Maisels
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    ABSTRACT: Although it is generally believed that preterm infants are at greater risk for the development of bilirubin-associated brain damage than term infants, quantification of the magnitude of this risk has proven elusive, as has a consensus among experts on the level of total serum bilirubin at which therapy should be initiated. Two large randomized studies have been performed that shed some light on the risk hyperbilirubinemia poses for preterm neonates and both studies are reviewed. Additional study is needed to further clarify the risk posed by hyperbilirubinemia in premature neonates and to frame guidelines for phototherapy and exchange transfusion that are more evidence-based.
    Seminars in Fetal and Neonatal Medicine 06/2010; 15(3):136-40. · 3.51 Impact Factor
  • Jon F Watchko
    Seminars in Fetal and Neonatal Medicine 12/2009; 15(3):121. · 3.51 Impact Factor
  • Jon F Watchko, Zhili Lin
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    ABSTRACT: The potential for genetic variation to modulate neonatal hyperbilirubinemia risk is increasingly being recognized. In particular, polymorphisms across three genes involved in bilirubin production and metabolism [glucose-6-phosphate dehydrogenase (G6PD), uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and solute carrier organic anion transporter polypeptide 1B1 (SLCO1B1)] may interact with each other and/or environmental contributors to produce significant hyperbilirubinemia. Variant gene co-expression including compound and synergistic heterozygosity enhances hyperbilirubinemia risk, contributing to the etiologic heterogeneity and complex nature of neonatal jaundice.
    Seminars in Fetal and Neonatal Medicine 12/2009; 15(3):169-75. · 3.51 Impact Factor
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    ABSTRACT: To determine whether glucose-6-phosphate dehydrogenase (G6PD), uridine-diphosphoglucuronosyltransferase 1A1 (UGT1A1), and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene variants occur at greater frequency in neonates with significant hyperbilirubinemia. Infants with gestational ages of >or=37 weeks and ages of <7 days were studied. Case subjects had >or=1 bilirubin level above the 95th percentile (high-risk zone), whereas control subjects had bilirubin levels of <40th percentile (low-risk zone) at study entry. A total of 153 case subjects (median bilirubin level: 15.7 mg/dL) and 299 control subjects (median bilirubin level: 4.6 mg/dL) were evaluated. There were no statistical differences in the frequencies of G6PD, UGT1A1, and SCLO1B1 gene variants between case and control subjects (G6PD: 5.2% vs 3.3%; UGT1A1: 14.4% vs 9.4%; SLCO1B1: 73.2% vs 73.6%). However, coexpression of the G6PD African A- mutation with UGT1A1 and/or SLCO1B1 variants was seen more frequently for case subjects. Case subjects more often demonstrated >or=2 factors contributing to hyperbilirubinemia, including ABO blood group heterospecificity in which the mother had blood group O (47.7% vs 11.4%), positive direct Coombs test results (33.3% vs 4%), sibling treated with phototherapy (16.3% vs 5.4%), maternal circulating blood group antibodies (10.5 vs 0.7%), maternal diabetes mellitus (13.1% vs 6.4%), and maternal East Asian ethnicity (6.5% vs 1.3%). Clinical contributors to hyperbilirubinemia were identified more frequently for case subjects but individually G6PD, UGT1A1, and SLCO1B1 variants were not. Coexpression of the G6PD African A- mutation with UGT1A1 and SLCO1B1 variants was seen more often for case subjects.
    PEDIATRICS 11/2009; 124(5):e868-77. · 4.47 Impact Factor
  • Jon F Watchko
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    ABSTRACT: African American neonates evidence a low incidence of hyperbilirubinemia yet account for more than 25% of the reported kernicterus cases in the USA. Glucose-6-phosphate dehydrogenase (G6PD) deficiency accounts for approximately 60%, and late preterm gestation and ABO hemolytic disease approximately 40% of these cases. Females heterozygous for G6PD A- harbor a population of G6PD-deficient red blood cells and are at risk for hyperbilirubinemia. Pre-discharge bilirubin measurement coupled with gestational age enhances the identification of neonates at hyperbilirubinemia risk. Parental education at the time of birth hospitalization discharge combined with timely follow-up may help to reduce the risk of developing hazardous hyperbilirubinemia.
    Seminars in Fetal and Neonatal Medicine 11/2009; 15(3):176-82. · 3.51 Impact Factor
  • PEDIATRICS 10/2009; 124(4):1193-8. · 4.47 Impact Factor

Publication Stats

1k Citations
483.06 Total Impact Points

Institutions

  • 1996–2013
    • University of Pittsburgh
      • • Division of Newborn Medicine
      • • Department of Neurology
      • • Department of Pediatrics
      • • Department of Critical Care Medicine
      • • School of Medicine
      Pittsburgh, PA, United States
  • 1988–2013
    • Magee-Womens Hospital
      • Department of Pediatrics
      Pittsburgh, Pennsylvania, United States
  • 2011
    • University of California, San Francisco
      San Francisco, California, United States
  • 2009
    • Beaumont Health System
      Detroit, Michigan, United States
  • 2003
    • William Beaumont Army Medical Center
      El Paso, Texas, United States
    • University of California, Los Angeles
      • Department of Pediatrics
      Los Angeles, CA, United States
    • University of Oslo
      • Department of Paediatrics
      Kristiania (historical), Oslo County, Norway
  • 1987–1998
    • University of Washington Seattle
      • Department of Pediatrics
      Seattle, WA, United States
  • 1994–1995
    • Mayo Foundation for Medical Education and Research
      • Department of Anesthesiology
      Scottsdale, AZ, United States