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Published in: ADHD Attention Deficit and Hyperactivity Disorders 2/2012

01-06-2012 | Original Article

Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood

Authors: Edna Grünblatt, Julia Geißler, Christian P. Jacob, Tobias Renner, Maja Müller, Jasmin Bartl, Silke Gross-Lesch, Peter Riederer, Klaus-Peter Lesch, Susanne Walitza, Manfred Gerlach, Angelika Schmitt

Published in: ADHD Attention Deficit and Hyperactivity Disorders | Issue 2/2012

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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common behavioural disorder that affects not only children and adolescents but also adults; however, diagnosis of adult ADHD is difficult because patients seem to have reduced externalized behaviour. ADHD is a multifactorial disorder in which many genes, all with small effects, are thought to cause the disorder in the presence of unfavourable environmental conditions. Therefore, in this pilot study, we explored the expression profile of a list of previously established candidate genes in peripheral blood samples from adult ADHD subjects (n = 108) and compared these results with those of healthy controls (n = 35). We demonstrate that combining the gene expression levels of dopamine transporter (SLC6A3), dopamine D5 receptor, tryptophan hydroxylase-1, and SNAP25 as predictors in a regression model resulted in sensitivity and specificity of over 80 % (ROC: max R 2 = 0.587, AUC = 0.917, P < 0.001, 95 % CI: 0.900–0.985). In conclusion, the combination of these four genes could represent a potential method for estimating risk and could be of diagnostic value for ADHD. Nevertheless, further investigation in a larger independent population including different subtypes of ADHD (inattentive, hyperactive, or combined type) patients is required to obtain more specific sets of biomarkers for each subtype as well as to differentiate between child, adolescent, and adulthood forms.
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Literature
go back to reference American Psychiatric Association (2000) American Psychiatric Association: diagnostic and statistical manual of mental disorders—DSM-IV-TR, 4th edn. American Psychiatric Association, Washington, DC American Psychiatric Association (2000) American Psychiatric Association: diagnostic and statistical manual of mental disorders—DSM-IV-TR, 4th edn. American Psychiatric Association, Washington, DC
go back to reference Burczynski ME, Dorner AJ (2006) Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics 7(2):187–202PubMedCrossRef Burczynski ME, Dorner AJ (2006) Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics 7(2):187–202PubMedCrossRef
go back to reference Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2(2):104–113PubMed Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2(2):104–113PubMed
go back to reference First MB, Spitzer RL, Gibbon M, Williams JBW (eds) (1997) Structured clinical interview for DSM-IV axis I disorders (SCID-I), clinician version. American Psychiatric Publishing Inc., Arlington, VA First MB, Spitzer RL, Gibbon M, Williams JBW (eds) (1997) Structured clinical interview for DSM-IV axis I disorders (SCID-I), clinician version. American Psychiatric Publishing Inc., Arlington, VA
go back to reference Forero DA, Arboleda GH, Vasquez R, Arboleda H (2009) Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants. J Psychiatry Neurosci 34(5):361–366PubMed Forero DA, Arboleda GH, Vasquez R, Arboleda H (2009) Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants. J Psychiatry Neurosci 34(5):361–366PubMed
go back to reference Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hummer A, Heine M, Jacob CP, Lesch KP, Casas M, Ribases M, Bosch R, Sanchez-Mora C, Gomez-Barros N, Fernandez-Castillo N, Bayes M, Halmoy A, Halleland H, Landaas ET, Fasmer OB, Knappskog PM, Heister AJ, Kiemeney LA, Kooij JJ, Boonstra AM, Kan CC, Asherson P, Faraone SV, Buitelaar JK, Haavik J, Cormand B, Ramos-Quiroga JA, Reif A (2010) Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology 35(3):656–664. doi:10.1038/npp.2009.170 PubMedCrossRef Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hummer A, Heine M, Jacob CP, Lesch KP, Casas M, Ribases M, Bosch R, Sanchez-Mora C, Gomez-Barros N, Fernandez-Castillo N, Bayes M, Halmoy A, Halleland H, Landaas ET, Fasmer OB, Knappskog PM, Heister AJ, Kiemeney LA, Kooij JJ, Boonstra AM, Kan CC, Asherson P, Faraone SV, Buitelaar JK, Haavik J, Cormand B, Ramos-Quiroga JA, Reif A (2010) Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology 35(3):656–664. doi:10.​1038/​npp.​2009.​170 PubMedCrossRef
go back to reference Gladkevich A, Kauffman HF, Korf J (2004) Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 28(3):559–576PubMedCrossRef Gladkevich A, Kauffman HF, Korf J (2004) Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 28(3):559–576PubMedCrossRef
go back to reference Glatt SJ, Everall IP, Kremen WS, Corbeil J, Sasik R, Khanlou N, Han M, Liew CC, Tsuang MT (2005) Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. Proc Natl Acad Sci USA 102(43):15533–15538. doi:10.1073/pnas.0507666102 PubMedCrossRef Glatt SJ, Everall IP, Kremen WS, Corbeil J, Sasik R, Khanlou N, Han M, Liew CC, Tsuang MT (2005) Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. Proc Natl Acad Sci USA 102(43):15533–15538. doi:10.​1073/​pnas.​0507666102 PubMedCrossRef
go back to reference Grünblatt E, Schlößer R, Fischer P, Fischer MO, Li J, Koutsilieri E, Wichart I, Sterba N, Rujescu D, Moller HJ, Adamcyk W, Dittrich B, Muller F, Oberegger K, Gatterer G, Jellinger KJ, Mostafaie N, Jungwirth S, Huber K, Tragl KH, Danielczyk W, Riederer P (2005) Oxidative stress related markers in the “VITA” and the centenarian projects. Neurobiol Aging 26(4):429–438PubMedCrossRef Grünblatt E, Schlößer R, Fischer P, Fischer MO, Li J, Koutsilieri E, Wichart I, Sterba N, Rujescu D, Moller HJ, Adamcyk W, Dittrich B, Muller F, Oberegger K, Gatterer G, Jellinger KJ, Mostafaie N, Jungwirth S, Huber K, Tragl KH, Danielczyk W, Riederer P (2005) Oxidative stress related markers in the “VITA” and the centenarian projects. Neurobiol Aging 26(4):429–438PubMedCrossRef
go back to reference Grünblatt E, Bartl J, Zehetmayer S, Ringel TM, Bauer P, Riederer P, Jacob CP (2009) Gene expression as peripheral biomarkers for sporadic Alzheimer’s disease. J Alzheimers Dis 16(3):627–634. doi:10.3233/JAD-2009-0996 PubMed Grünblatt E, Bartl J, Zehetmayer S, Ringel TM, Bauer P, Riederer P, Jacob CP (2009) Gene expression as peripheral biomarkers for sporadic Alzheimer’s disease. J Alzheimers Dis 16(3):627–634. doi:10.​3233/​JAD-2009-0996 PubMed
go back to reference Grünblatt E, Zehetmayer S, Jacob CP, Muller T, Jost WH, Riederer P (2010) Pilot study: peripheral biomarkers for diagnosing sporadic Parkinson’s disease. J Neural Transm. doi:10.1007/s00702-010-0509-1 Grünblatt E, Zehetmayer S, Jacob CP, Muller T, Jost WH, Riederer P (2010) Pilot study: peripheral biomarkers for diagnosing sporadic Parkinson’s disease. J Neural Transm. doi:10.​1007/​s00702-010-0509-1
go back to reference Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29(1):8–16PubMedCrossRef Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29(1):8–16PubMedCrossRef
go back to reference Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A, Reif A, Walitza S, Romanos M, Strobel A, Brocke B, Schafer H, Schmidtke A, Boning J, Lesch KP (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257(6):309–317. doi:10.1007/s00406-007-0722-6 PubMedCrossRef Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A, Reif A, Walitza S, Romanos M, Strobel A, Brocke B, Schafer H, Schmidtke A, Boning J, Lesch KP (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257(6):309–317. doi:10.​1007/​s00406-007-0722-6 PubMedCrossRef
go back to reference Johansson S, Halmoy A, Mavroconstanti T, Jacobsen KK, Landaas ET, Reif A, Jacob C, Boreatti-Hummer A, Kreiker S, Lesch KP, Kan CC, Kooij JJ, Kiemeney LA, Buitelaar JK, Franke B, Ribases M, Bosch R, Bayes M, Casas M, Ramos-Quiroga JA, Cormand B, Knappskog P, Haavik J (2010) Common variants in the TPH1 and TPH2 regions are not associated with persistent ADHD in a combined sample of 1,636 adult cases and 1,923 controls from four European populations. Am J Med Genet B Neuropsychiatr Genet 153B(5):1008–1015. doi:10.1002/ajmg.b.31067 PubMed Johansson S, Halmoy A, Mavroconstanti T, Jacobsen KK, Landaas ET, Reif A, Jacob C, Boreatti-Hummer A, Kreiker S, Lesch KP, Kan CC, Kooij JJ, Kiemeney LA, Buitelaar JK, Franke B, Ribases M, Bosch R, Bayes M, Casas M, Ramos-Quiroga JA, Cormand B, Knappskog P, Haavik J (2010) Common variants in the TPH1 and TPH2 regions are not associated with persistent ADHD in a combined sample of 1,636 adult cases and 1,923 controls from four European populations. Am J Med Genet B Neuropsychiatr Genet 153B(5):1008–1015. doi:10.​1002/​ajmg.​b.​31067 PubMed
go back to reference Kim JW, Biederman J, Arbeitman L, Fagerness J, Doyle AE, Petty C, Perlis RH, Purcell S, Smoller JW, Faraone SV, Sklar P (2007) Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 144B(6):781–790. doi:10.1002/ajmg.b.30522 PubMedCrossRef Kim JW, Biederman J, Arbeitman L, Fagerness J, Doyle AE, Petty C, Perlis RH, Purcell S, Smoller JW, Faraone SV, Sklar P (2007) Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 144B(6):781–790. doi:10.​1002/​ajmg.​b.​30522 PubMedCrossRef
go back to reference Lara C, Fayyad J, de Graaf R, Kessler RC, Aguilar-Gaxiola S, Angermeyer M, Demytteneare K, de Girolamo G, Haro JM, Jin R, Karam EG, Lepine JP, Mora ME, Ormel J, Posada-Villa J, Sampson N (2009) Childhood predictors of adult attention-deficit/hyperactivity disorder: results from the World Health Organization World Mental Health Survey Initiative. Biol Psychiatry 65(1):46–54. doi:10.1016/j.biopsych.2008.10.005 PubMedCrossRef Lara C, Fayyad J, de Graaf R, Kessler RC, Aguilar-Gaxiola S, Angermeyer M, Demytteneare K, de Girolamo G, Haro JM, Jin R, Karam EG, Lepine JP, Mora ME, Ormel J, Posada-Villa J, Sampson N (2009) Childhood predictors of adult attention-deficit/hyperactivity disorder: results from the World Health Organization World Mental Health Survey Initiative. Biol Psychiatry 65(1):46–54. doi:10.​1016/​j.​biopsych.​2008.​10.​005 PubMedCrossRef
go back to reference Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274(5292):1527–1531PubMedCrossRef Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274(5292):1527–1531PubMedCrossRef
go back to reference Mehler-Wex C, Duvigneau JC, Hartl RT, Ben-Shachar D, Warnke A, Gerlach M (2006) Increased mRNA levels of the mitochondrial complex I 75-kDa subunit. A potential peripheral marker of early onset schizophrenia? Eur Child Adolesc Psychiatry 15(8):504–507. doi:10.1007/s00787-006-0560-5 PubMedCrossRef Mehler-Wex C, Duvigneau JC, Hartl RT, Ben-Shachar D, Warnke A, Gerlach M (2006) Increased mRNA levels of the mitochondrial complex I 75-kDa subunit. A potential peripheral marker of early onset schizophrenia? Eur Child Adolesc Psychiatry 15(8):504–507. doi:10.​1007/​s00787-006-0560-5 PubMedCrossRef
go back to reference Noori-Daloii MR, Kheirollahi M, Mahbod P, Mohammadi F, Astaneh AN, Zarindast MR, Azimi C, Mohammadi MR (2010) Alpha- and beta-synucleins mRNA expression in lymphocytes of schizophrenia patients. Genet Test Mol Biomarkers 14(5):725–729. doi:10.1089/gtmb.2010.0050 PubMedCrossRef Noori-Daloii MR, Kheirollahi M, Mahbod P, Mohammadi F, Astaneh AN, Zarindast MR, Azimi C, Mohammadi MR (2010) Alpha- and beta-synucleins mRNA expression in lymphocytes of schizophrenia patients. Genet Test Mol Biomarkers 14(5):725–729. doi:10.​1089/​gtmb.​2010.​0050 PubMedCrossRef
go back to reference Renner TJ, Walitza S, Dempfle A, Eckert L, Romanos M, Gerlach M, Schafer H, Warnke A, Lesch KP, Jacob C (2008) Allelic variants of SNAP25 in a family-based sample of ADHD. J Neural Transm 115(2):317–321. doi:10.1007/s00702-007-0840-3 PubMedCrossRef Renner TJ, Walitza S, Dempfle A, Eckert L, Romanos M, Gerlach M, Schafer H, Warnke A, Lesch KP, Jacob C (2008) Allelic variants of SNAP25 in a family-based sample of ADHD. J Neural Transm 115(2):317–321. doi:10.​1007/​s00702-007-0840-3 PubMedCrossRef
go back to reference Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR (2007) Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci USA 104(3):955–960PubMedCrossRef Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR (2007) Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci USA 104(3):955–960PubMedCrossRef
go back to reference Stergiakouli E, Thapar A (2010) Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatr Dis Treat 6:551–560. doi:10.2147/NDT.S11322 PubMedCrossRef Stergiakouli E, Thapar A (2010) Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatr Dis Treat 6:551–560. doi:10.​2147/​NDT.​S11322 PubMedCrossRef
go back to reference Sullivan PF, Fan C, Perou CM (2006) Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 141(3):261–268 Sullivan PF, Fan C, Perou CM (2006) Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 141(3):261–268
go back to reference Taurines R, Thome J, Duvigneau JC, Forbes-Robertson S, Yang L, Klampfl K, Romanos J, Muller S, Gerlach M, Mehler-Wex C (2010) Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia. Eur Child Adolesc Psychiatry 19(5):441–448. doi:10.1007/s00787-009-0074-z PubMedCrossRef Taurines R, Thome J, Duvigneau JC, Forbes-Robertson S, Yang L, Klampfl K, Romanos J, Muller S, Gerlach M, Mehler-Wex C (2010) Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia. Eur Child Adolesc Psychiatry 19(5):441–448. doi:10.​1007/​s00787-009-0074-z PubMedCrossRef
go back to reference Taurines R, Grünblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschlager L, Walitza S, Renner T, Gerlach M, Thome J, Romanos M (2011) Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatry 12(Suppl 1):104–108. doi:10.3109/15622975.2011.600297 PubMed Taurines R, Grünblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschlager L, Walitza S, Renner T, Gerlach M, Thome J, Romanos M (2011) Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatry 12(Suppl 1):104–108. doi:10.​3109/​15622975.​2011.​600297 PubMed
go back to reference Tsuang MT, Nossova N, Yager T, Tsuang MM, Guo SC, Shyu KG, Glatt SJ, Liew CC (2005) Assessing the validity of blood-based gene expression profiles for the classification of schizophrenia and bipolar disorder: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 133B(1):1–5. doi:10.1002/ajmg.b.30161 PubMedCrossRef Tsuang MT, Nossova N, Yager T, Tsuang MM, Guo SC, Shyu KG, Glatt SJ, Liew CC (2005) Assessing the validity of blood-based gene expression profiles for the classification of schizophrenia and bipolar disorder: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 133B(1):1–5. doi:10.​1002/​ajmg.​b.​30161 PubMedCrossRef
go back to reference Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034PubMedCrossRef Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034PubMedCrossRef
go back to reference Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, Herpertz-Dahlmann B, Remschmidt H, Smidt J, Linder M, Flierl L, Knolker U, Friedel S, Schafer H, Gross C, Hebebrand J, Warnke A, Lesch KP (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10(12):1126–1132. doi:10.1038/sj.mp.4001734 PubMedCrossRef Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, Herpertz-Dahlmann B, Remschmidt H, Smidt J, Linder M, Flierl L, Knolker U, Friedel S, Schafer H, Gross C, Hebebrand J, Warnke A, Lesch KP (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10(12):1126–1132. doi:10.​1038/​sj.​mp.​4001734 PubMedCrossRef
go back to reference Walitza S, Scherag A, Renner TJ, Hinney A, Remschmidt H, Herpertz-Dahlmann B, Schulz E, Schafer H, Lange KW, Wewetzer C, Gerlach M (2008) Transmission disequilibrium studies in early onset of obsessive-compulsive disorder for polymorphisms in genes of the dopaminergic system. J Neural Transm 115(7):1071–1078. doi:10.1007/s00702-008-0051-6 PubMedCrossRef Walitza S, Scherag A, Renner TJ, Hinney A, Remschmidt H, Herpertz-Dahlmann B, Schulz E, Schafer H, Lange KW, Wewetzer C, Gerlach M (2008) Transmission disequilibrium studies in early onset of obsessive-compulsive disorder for polymorphisms in genes of the dopaminergic system. J Neural Transm 115(7):1071–1078. doi:10.​1007/​s00702-008-0051-6 PubMedCrossRef
Metadata
Title
Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood
Authors
Edna Grünblatt
Julia Geißler
Christian P. Jacob
Tobias Renner
Maja Müller
Jasmin Bartl
Silke Gross-Lesch
Peter Riederer
Klaus-Peter Lesch
Susanne Walitza
Manfred Gerlach
Angelika Schmitt
Publication date
01-06-2012
Publisher
Springer Vienna
Published in
ADHD Attention Deficit and Hyperactivity Disorders / Issue 2/2012
Print ISSN: 1866-6116
Electronic ISSN: 1866-6647
DOI
https://doi.org/10.1007/s12402-012-0074-6

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