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Joseph T. Glessner,
Kai Wang,
Guiqing Cai,
Olena Korvatska,
Cecilia E. Kim,
Shawn Wood,
Haitao Zhang,
Annette Estes,
Camille W. Brune,
Jonathan P. Bradfield, [......],
Hilary Coon,
James S. Sutcliffe,
Nancy J. Minshew,
Struan F. A. Grant,
Maja Bucan,
Edwin H. Cook,
Joseph D. Buxbaum,
Bernie Devlin,
Gerard D. Schellenberg,
Hakon Hakonarson
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[show abstract]
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ABSTRACT: Psychotropic medications, including the atypical antipsychotics, have historically been scrutinized for cardiac effects and risk of sudden death. Aripiprazole is an atypical antipsychotic approved for pediatric use in schizophrenia, bipolar I disorder, and autistic disorder. Adult studies have evaluated aripiprazole's effects on electrocardiograms, but no pediatric studies have been published to date.
Electrocardiographic data were collected from children and adolescents participating in a 14-week, prospective, open-label study (n=25) of aripiprazole for irritability in pervasive developmental disorder not otherwise specified and Asperger's disorder. A 12-lead electrocardiogram was obtained at the baseline and end point visits. The electrocardiograms were evaluated for abnormal findings, and the PR, QRS, QT(c), and RR intervals were recorded. The QT interval was corrected using Bazett's, United States Food and Drug Administration (FDA) Pharmacology Division, and Fridericia's formulas.
Twenty-four subjects received both baseline and posttreatment electrocardiograms. The mean age was 8.6 years (range 5-17 years). The average final aripiprazole dose was 7.8 mg/day (range 2.5-15 mg/day). There were no significant differences noted with the PR, QRS, RR, and QT(c) intervals after aripiprazole therapy. Also, there was no significant correlation between the dose given and the percent change in the QT(c). No post-treatment QT(c) exceeded 440 ms.
To our knowledge, this is the first systematic evaluation of the cardiac effects of aripiprazole in children and adolescents. The results are consistent with previously published literature in adults that aripiprazole has no significant cardiac effects and can be deemed a low risk for causing sudden death. It will be important to confirm these findings in a randomized controlled trial.
Journal of child and adolescent psychopharmacology 07/2012; 22(4):277-83. · 2.59 Impact Factor
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Richard Anney,
Lambertus Klei,
Dalila Pinto,
Joana Almeida,
Elena Bacchelli,
Gillian Baird,
Nadia Bolshakova,
Sven Bölte,
Patrick F Bolton,
Thomas Bourgeron, [......],
Edwin H Cook,
Louise Gallagher,
Michael Gill,
Joachim Hallmayer,
Andrew D Paterson,
James S Sutcliffe,
Peter Szatmari,
Veronica J Vieland,
Hakon Hakonarson,
Bernie Devlin
[show abstract]
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ABSTRACT: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Human Molecular Genetics 07/2012; 21(21):4781-92. · 7.64 Impact Factor
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ABSTRACT: Individuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies.
The aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism.
This is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months.
Twenty-one (84 %) of 25 subjects ages 12-21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3-12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n = 1; nonresponse, n = 1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range -3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p ≤ 0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p ≤ 0.0001).
Paliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.
Psychopharmacologia 05/2012; 223(2):237-45. · 4.08 Impact Factor
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ABSTRACT: Serotonin and its precursor tryptophan have long been implicated in the pathophysiology of autistic disorder (autism). Recent
genetic evidence implicates involvement of a gene encoding tryptophan 2,3-dioxygenase, a rate-limiting enzyme in tryptophan's
major metabolic pathway, the kynurenine pathway, in autism. To test activity of the kynurenine pathway in autism, plasma kynurenine
levels were measured in 30 drug-free autistic children (mean age (SD)=6 years 0 months (2 years 9 months)) and 29 age-, race-
and gender-matched healthy comparison subjects (mean age (SD)=6 years 5 months (2 years 6 months)) using high-performance
liquid chromatography. No difference was found in plasma kynurenine levels between the study groups. In the autistic children,
plasma kynurenine levels did not correlate with autistic behaviors or IQ. These results do not support a role for abnormal
global function of the kynurenine pathway; however, the status of this pathway in the brain remains unknown.
Journal of Developmental and Physical Disabilities 04/2012; 18(4):419-426. · 0.89 Impact Factor
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Jillian P Casey,
Tiago Magalhaes,
Judith M Conroy,
Regina Regan,
Naisha Shah,
Richard Anney,
Denis C Shields,
Brett S Abrahams,
Joana Almeida,
Elena Bacchelli, [......],
Stephen W Scherer,
James S Sutcliffe,
Peter Szatmari,
Veronica J Vieland,
Ellen M Wijsman,
Andrew Green,
Michael Gill,
Louise Gallagher,
Astrid Vicente,
Sean Ennis
[show abstract]
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ABSTRACT: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Human Genetics 10/2011; 131(4):565-79. · 5.07 Impact Factor
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Journal of clinical psychopharmacology 10/2011; 31(5):673-5. · 5.09 Impact Factor
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Journal of child and adolescent psychopharmacology 06/2011; 21(3):287-90. · 2.59 Impact Factor
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ABSTRACT: Fragile X syndrome (FXS) is the most common inherited form of developmental disability and most common single gene cause of autism. Persons with FXS frequently exhibit irritable behavior marked by aggression, self-injury, and severe tantrums. Despite frequent clinical use of atypical antipsychotic drugs to target this behavioral cluster, no systematic trials to date have assessed the efficacy and safety of these drugs in persons with FXS.
We conducted a prospective open-label 12-week trial of aripiprazole in 12 persons aged 6-25 years (mean age, 14.3 years) with FXS who were free of concomitant psychoactive drugs.
Aripiprazole use (mean dose, 9.8 mg/day) was associated with treatment response (defined by a Clinical Global Impressions-Improvement scale score of much improved or very much improved and a ≥ 25% improvement on the Aberrant Behavior Checklist-Irritability subscale) in 10 of 12 (87%) persons. Two individuals (13%) discontinued aripiprazole prior to study completion due to adverse events. One discontinuation was due to akathisia, mild drooling, and mild tiredness and the other due to moderate tiredness and moderate drooling. No significant changes in vital signs including weight or laboratory measures occurred during treatment with aripiprazole.
Aripiprazole was generally safe and well tolerated and was associated with significant improvement in irritable behavior. Given these findings, a double-blind, placebo-controlled study of aripiprazole in FXS is warranted.
Psychopharmacologia 02/2011; 216(1):85-90. · 4.08 Impact Factor
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Richard Anney,
Lambertus Klei,
Dalila Pinto,
Regina Regan,
Judith Conroy,
Tiago R Magalhaes,
Catarina Correia,
Brett S Abrahams,
Nuala Sykes,
Alistair T Pagnamenta, [......],
Gerard D Schellenberg,
Stephen W Scherer,
James S Sutcliffe,
Peter Szatmari,
Astrid M Vicente,
Veronica J Vieland,
Ellen M Wijsman,
Bernie Devlin,
Sean Ennis,
Joachim Hallmayer
[show abstract]
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ABSTRACT: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Human Molecular Genetics 10/2010; 19(20):4072-82. · 7.64 Impact Factor
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ABSTRACT: Aripiprazole was recently US FDA-approved to treat irritability in children and adolescents with autistic disorder aged 6-17 years. There are currently only two psychotropics approved by the FDA to treat irritability in the autistic population. This drug profile will discuss available studies of aripiprazole in individuals with pervasive developmental disorders, two of which led to its recent FDA approval. We will discuss the efficacy, as well as the safety and tolerability of the drug documented in these studies. In addition, the chemistry, pharmacokinetics, metabolism and mechanism of action of aripiprazole will be reviewed.
Pediatric Health 09/2010; 4(4):375-381.
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Dalila Pinto,
Alistair T Pagnamenta,
Lambertus Klei,
Richard Anney,
Daniele Merico,
Regina Regan,
Judith Conroy,
Tiago R Magalhaes,
Catarina Correia,
Brett S Abrahams, [......],
Andrew D Paterson,
Margaret A Pericak-Vance,
Gerard D Schellenberg,
Peter Szatmari,
Astrid M Vicente,
Veronica J Vieland,
Ellen M Wijsman,
Stephen W Scherer,
James S Sutcliffe,
Catalina Betancur
[show abstract]
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ABSTRACT: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Nature 07/2010; 466(7304):368-72. · 36.28 Impact Factor
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ABSTRACT: Autism spectrum disorders (ASDs) are childhood onset developmental disorders characterized by impairment of social skills and repetitive behavior, and also for classic autistic disorder, a significant impairment of communication. In addition to these core symptom domains, persons with ASDs frequently exhibit interfering behavioral symptoms, including irritability marked by aggression, self-injurious behavior, and severe tantrums. Aripiprazole is an atypical or newer generation antipsychotic with a unique mechanism of action impacting dopaminergic and serotonergic neurotransmission. The drug has been found efficacious for several indications, including most recently for use targeting irritability associated with autistic disorder in youth. Fragile X syndrome is the most common inherited cause of developmental disability and the most common known single gene cause of ASDs. As in idiopathic ASDs, irritable behavior is often exhibited by persons with fragile X syndrome. However, research to date in this disorder has not focused on this target symptom cluster. An initial pilot study has begun to assess the impact of aripiprazole on irritability in youth with fragile X syndrome.
Journal of the American Society for Experimental NeuroTherapeutics 07/2010; 7(3):258-63. · 5.38 Impact Factor
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L Eugene Arnold,
Cristan Farmer,
Helena Chmura Kraemer,
Mark Davies,
Andrea Witwer,
Shirley Chuang,
Robert DiSilvestro,
Christopher J McDougle,
James McCracken,
Benedetto Vitiello,
Michael G Aman,
Lawrence Scahill, David J Posey,
Naomi B Swiezy
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ABSTRACT: The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritability in autistic disorder. This paper explores moderators and mediators of this effect.
Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results.
Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo.
The benefit-risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems nonspecifically predict better outcome. Mineral interactions with risperidone deserve further study.
Journal of child and adolescent psychopharmacology 04/2010; 20(2):83-93. · 2.59 Impact Factor
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Journal of child and adolescent psychopharmacology 02/2010; 20(1):75-8. · 2.59 Impact Factor
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Lauren A. Weiss,
Dan E. Arking,
Mark J. Daly,
Aravinda Chakravarti,
Camille W. Brune,
Kristen West,
Ashley O|[rsquo]|Connor,
Gina Hilton,
Rebecca L. Tomlinson,
Andrew B. West, [......],
Alison Schonwald,
Esau Simmons,
Leonard A. Rappaport,
Julie Gauthier,
Laurent Mottron,
Ridha Joober,
Guy Rouleau,
Karola Rehnstrom,
Lennart von Wendt,
Leena Peltonen
[show abstract]
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ABSTRACT: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success
Nature 10/2009; 461(7265):802-808. · 36.28 Impact Factor
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MD Ronald L. Lindsay,
L. Eugene Arnold,
Michael G. Aman,
Benedetto Vitiello, David J. Posey,
Christopher J. McDougle,
Lawrence Scahill,
Maryellen Pachler,
James T. McCracken,
Elaine Tierney,
Dawn Bozzolo
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ABSTRACT: Background Risperidone may be effective in improving tantrums, aggression, or self‐injurious behaviour in children with autism, but often leads to weight gain. Method Using a quantitative Food Frequency Questionnaire (FFQ), we prospectively examined the nutritional intake of 20 children with autism participating in a randomised placebo‐controlled trial of risperidone for disruptive behaviours. Results At baseline, the mean intakes for macronutrients, vitamins and minerals exceeded Dietary Reference Intakes (DRIs). However there was substantial inter‐participant variability, with individual deficiencies (<80% of DRI) in the intake of calcium (9 of 20 participants), pantothenic acid (6 of 20), vitamin D (5 of 20) and vitamin K (8 of 20). For the participants for whom FFQs were available, there was an increase in weight and an increase in vitamin K intake after 2 months of risperidone treatment (n = 9) compared to placebo (n = 8). An additional 4 months of risperidone treatment (n = 8) did not result in significant changes in reported nutritional balance. Conclusion These pilot data suggest that treatment with risperidone did not significantly affect the nutritional balance of this small group of children.
07/2009; 31(4):204-209.
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ABSTRACT: The aim of this study was to determine the effectiveness and tolerability of aripiprazole for irritability in pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's disorder.
This is a 14-week, prospective, open-label investigation of aripiprazole in 25 children and adolescents diagnosed with PDD-NOS or Asperger's disorder. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I).
Twenty-five subjects, ages 5-17 years (mean 8.6 years) received a mean final aripiprazole dosage of 7.8 mg/day (range 2.5-15 mg/day). Full-scale intelligence quotient (IQ) scores ranged from 48 to 122 (mean 84). Twenty-two (88%) of 25 subjects were responders in regard to interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-I of 1 or 2 (very much or much improved) and a 25% or greater improvement on the ABC-I. The final mean CGI-I was 1.6 (p <or= 0.0001). ABC-I scores ranged from 18 to 43 (mean 29) at baseline, whereas scores at week 14 ranged from 0 to 27 (mean 8.1) (p <or= 0.001). Aripiprazole was well tolerated. Mild extrapyramidal symptoms (EPS) were reported in 9 subjects. Age- and sex-normed body mass index (BMI) increased from a mean value of 20.3 at baseline to 21.1 at end point (p <or= 0.04). Prolactin significantly decreased from a mean value of 9.3 at baseline to 2.9 at end point (p <or= 0.0001). No subject exited the study due to a drug-related adverse event.
These preliminary data suggest that aripiprazole may be effective and well tolerated for severe irritability in pediatric patients with PDD-NOS or Asperger's disorder. Larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of aripiprazole in this understudied population.
Journal of child and adolescent psychopharmacology 06/2009; 19(3):265-74. · 2.59 Impact Factor
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Joseph T Glessner,
Kai Wang,
Guiqing Cai,
Olena Korvatska,
Cecilia E Kim,
Shawn Wood,
Haitao Zhang,
Annette Estes,
Camille W Brune,
Jonathan P Bradfield, [......],
Hilary Coon,
James S Sutcliffe,
Nancy J Minshew,
Struan F A Grant,
Maja Bucan,
Edwin H Cook,
Joseph D Buxbaum,
Bernie Devlin,
Gerard D Schellenberg,
Hakon Hakonarson
[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Nature 05/2009; 459(7246):569-73. · 36.28 Impact Factor
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Joseph T. Glessner,
Kai Wang,
Guiqing Cai,
Olena Korvatska,
Cecilia E. Kim,
Shawn Wood,
Haitao Zhang,
Annette Estes,
Camille W. Brune,
Jonathan P. Bradfield, [......],
Hilary Coon,
James S. Sutcliffe,
Nancy J. Minshew,
Struan F. A. Grant,
Maja Bucan,
Edwin H. Cook,
Joseph D. Buxbaum,
Bernie Devlin,
Gerard D. Schellenberg,
Hakon Hakonarson
Nature 04/2009; 459(7246):569-573. · 36.28 Impact Factor
