William Slikker

Summary

Affiliation: Food and Drug Administration
Country: USA

Publications

  1. ncbi request reprint Systems biology approaches for toxicology
    William Slikker
    National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, Arkansas 72079 9502, USA
    J Appl Toxicol 27:201-17. 2007
  2. doi request reprint Advancing global health through regulatory science research: summary of the Global Summit on Regulatory Science Research and Innovation
    William Slikker
    United States Food and Drug Administration, Silver Spring, MD 20993, USA
    Regul Toxicol Pharmacol 62:471-3. 2012
  3. ncbi request reprint Ketamine-induced neuronal cell death in the perinatal rhesus monkey
    William Slikker
    Division of Neurotoxicology, National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, AR 72079 0502, USA
    Toxicol Sci 98:145-58. 2007
  4. doi request reprint Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain
    Xiaoju Zou
    Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA
    Int J Dev Neurosci 27:727-31. 2009
  5. pmc Potential neurotoxicity of ketamine in the developing rat brain
    Xiaoju Zou
    Division of Neurotoxicology, National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, Arkansas 72079, USA
    Toxicol Sci 108:149-58. 2009
  6. doi request reprint Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture
    Cheng Wang
    Division of Neurotoxicology, National Center for Toxicological Research US Food and Drug Administration, HFT 132 Jefferson, AR, USA
    Neurotoxicology 29:613-20. 2008
  7. ncbi request reprint Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture
    Cheng Wang
    Division of Neurotoxicology, National Center for Toxicological Research Food and Drug Administration, Jefferson, Arkansas 72079 0502, USA
    Toxicol Sci 91:192-201. 2006
  8. pmc Ketamine-induced neuronal damage and altered N-methyl-D-aspartate receptor function in rat primary forebrain culture
    Fang Liu
    Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079 0502, USA
    Toxicol Sci 131:548-57. 2013
  9. doi request reprint Brain microvessel endothelial cells responses to gold nanoparticles: In vitro pro-inflammatory mediators and permeability
    William J Trickler
    Neurochemistry Laboratory, Division of Neurotoxicology, National Center of Toxicological Research FDA, Jefferson, Arkansas, USA
    Nanotoxicology 5:479-92. 2011
  10. doi request reprint Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey
    Xiaoju Zou
    Division of Neurotoxicology, National Center for Toxicological Research U S Food and Drug Administration, Jefferson, AR 72079, USA
    Neurotoxicol Teratol 33:592-7. 2011

Collaborators

Detail Information

Publications55

  1. ncbi request reprint Systems biology approaches for toxicology
    William Slikker
    National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, Arkansas 72079 9502, USA
    J Appl Toxicol 27:201-17. 2007
    ..Published in 2007 John Wiley & Sons, Ltd...
  2. doi request reprint Advancing global health through regulatory science research: summary of the Global Summit on Regulatory Science Research and Innovation
    William Slikker
    United States Food and Drug Administration, Silver Spring, MD 20993, USA
    Regul Toxicol Pharmacol 62:471-3. 2012
    ....
  3. ncbi request reprint Ketamine-induced neuronal cell death in the perinatal rhesus monkey
    William Slikker
    Division of Neurotoxicology, National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, AR 72079 0502, USA
    Toxicol Sci 98:145-58. 2007
    ..However, a shorter duration of ketamine anesthesia (3 h) did not result in neuronal cell death in the 5-day-old monkey...
  4. doi request reprint Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain
    Xiaoju Zou
    Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA
    Int J Dev Neurosci 27:727-31. 2009
    ..However, anesthetic durations of 9h or greater are associated with significant brain cell death in the frontal cortex. Thus, the threshold duration below which no neurotoxicity would be expected is somewhere between 3 and 9h...
  5. pmc Potential neurotoxicity of ketamine in the developing rat brain
    Xiaoju Zou
    Division of Neurotoxicology, National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, Arkansas 72079, USA
    Toxicol Sci 108:149-58. 2009
    ..Ketamine-induced cell death appears to be apoptotic in nature and closely associated with enhanced NMDA receptor subunit mRNA expression...
  6. doi request reprint Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture
    Cheng Wang
    Division of Neurotoxicology, National Center for Toxicological Research US Food and Drug Administration, HFT 132 Jefferson, AR, USA
    Neurotoxicology 29:613-20. 2008
    ..These data indicate a role for nitric oxide in the enhanced degeneration induced by ketamine in vitro and also suggest that blocking neuronal nitric oxide synthase (nNOS) may help reduce the risk of ketamine in pediatrics...
  7. ncbi request reprint Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture
    Cheng Wang
    Division of Neurotoxicology, National Center for Toxicological Research Food and Drug Administration, Jefferson, Arkansas 72079 0502, USA
    Toxicol Sci 91:192-201. 2006
    ..Ketamine-induced effects were blocked by NR1 antisenses and SN-50. These data suggest that NR1 antisenses and SN-50 offer neuroprotection from the enhanced degeneration induced by ketamine in vitro...
  8. pmc Ketamine-induced neuronal damage and altered N-methyl-D-aspartate receptor function in rat primary forebrain culture
    Fang Liu
    Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR 72079 0502, USA
    Toxicol Sci 131:548-57. 2013
    ..L-Carnitine appears to be a promising agent in preventing or reversing ketamine's toxic effects on neurons at an early developmental stage...
  9. doi request reprint Brain microvessel endothelial cells responses to gold nanoparticles: In vitro pro-inflammatory mediators and permeability
    William J Trickler
    Neurochemistry Laboratory, Division of Neurotoxicology, National Center of Toxicological Research FDA, Jefferson, Arkansas, USA
    Nanotoxicology 5:479-92. 2011
    ..Together, these data suggest the responses of the cerebral microvasculature to Au-NPs have a significant relationship with the Au-NPs unique size-dependent physiochemical properties...
  10. doi request reprint Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey
    Xiaoju Zou
    Division of Neurotoxicology, National Center for Toxicological Research U S Food and Drug Administration, Jefferson, AR 72079, USA
    Neurotoxicol Teratol 33:592-7. 2011
    ..These data suggest that prolonged exposure to inhaled anesthetics (a combination of N(2)O and ISO) in the developing rhesus monkey results in neuronal damage, and that the cell death observed is apoptotic and necrotic in nature...
  11. doi request reprint Effects of copper nanoparticles on rat cerebral microvessel endothelial cells
    William J Trickler
    Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research FDA, Jefferson, AR 72079, USA
    Nanomedicine (Lond) 7:835-46. 2012
    ..The purpose of the current study was to determine whether copper nanoparticles (Cu-NPs) can induce the release of proinflammatory mediators that influence the restrictive characteristics of the blood-brain barrier...
  12. doi request reprint A minimally invasive, translational biomarker of ketamine-induced neuronal death in rats: microPET Imaging using 18F-annexin V
    Xuan Zhang
    Division of Neurotoxicology, National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, Arkansas 72079, USA
    Toxicol Sci 111:355-61. 2009
    ....
  13. doi request reprint Strategies and experimental models for evaluating anesthetics: effects on the developing nervous system
    Cheng Wang
    Division of Neurotoxicology, National Center for Toxicological Research F3900 NCTR Road, Jefferson, AR 72079 9502, USA
    Anesth Analg 106:1643-58. 2008
    ..Our focus on ketamine should not be construed as implying that the risk of neurodegeneration with ketamine is greater, or less, than with other anesthetics. We are simply describing the effects where we have the most preclinical data...
  14. ncbi request reprint Anesthetic-induced oxidative stress and potential protection
    Cheng Wang
    National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, AR, USA
    ScientificWorldJournal 10:1473-82. 2010
    ..However, more evidence is necessary to in order verify the role of the NMDA receptor subunit NR1 and ROS in anesthetic-induced neurodegeneration...
  15. ncbi request reprint Application of microPET imaging approaches in the study of pediatric anesthetic-induced neuronal toxicity
    Xuan Zhang
    Division of Neurotoxicology, National Center for Toxicological Research NCTR FDA, Jefferson, AR 72079, USA
    J Appl Toxicol 33:861-8. 2013
    ..The main aim of this review was to describe molecular imaging approaches that have been used in the study of pediatric anesthetic-induced neuronal toxicity...
  16. ncbi request reprint Porcine brain microvessel endothelial cells show pro-inflammatory response to the size and composition of metallic nanoparticles
    William J Trickler
    Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
    Drug Metab Rev 46:224-31. 2014
    ..Together, these data suggest that the composition and size of NPs can cause significant pro-inflammatory response that can influence the integrity of the BBB...
  17. ncbi request reprint Protective effect of acetyl-l-carnitine on propofol-induced toxicity in embryonic neural stem cells
    Fang Liu
    Division of Neurotoxicology, National Center for Toxicological Research Food and Drug Administration, Jefferson, AR 72079, USA Electronic address
    Neurotoxicology 42:49-57. 2014
    ....
  18. ncbi request reprint Effect of prolonged ketamine exposure on cardiovascular physiology in pregnant and infant rhesus monkeys (Macaca mulatta)
    Charlotte E Hotchkiss
    The Bionetics Corporation, National Center for Toxicological Research FDA, Jefferson, AR, USA
    J Am Assoc Lab Anim Sci 46:21-8. 2007
    ..Investigators should consider these effects when designing experiments and evaluating experimental outcomes in monkeys...
  19. doi request reprint Utilization of neural stem cell-derived models to study anesthesia-related toxicity and preventative approaches
    Cheng Wang
    Division of Neurotoxicology, National Center for Toxicological Research NCTR FDA, Jefferson, AR, USA
    Mol Neurobiol 48:302-7. 2013
    ....
  20. doi request reprint Preclinical assessment of ketamine
    Cheng Wang
    Division of Neurotoxicology, National Center for Toxicological Research NCTR FDA, Jefferson, AR 72079 9501, USA
    CNS Neurosci Ther 19:448-53. 2013
    ....
  21. pmc Neuroprotective efficacy of a new brain-penetrating C-Abl inhibitor in a murine Parkinson's disease model
    Syed Z Imam
    Division of Neurotoxicology, US FDA National Center for Toxicological Research, Jefferson, Arkansas, United States of America
    PLoS ONE 8:e65129. 2013
    ..We propose that compounds of the INNO-406 class of Abl inhibitors will be useful new neuroprotective drugs for the treatment of PD-like pathology in preclinical systems that should be easily translated to the clinic...
  22. ncbi request reprint Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity
    Kathleen A Haberny
    Center for Drug Evaluation and Research, U S Food and Drug Administration, Rockville, Maryland 20857, USA
    Toxicol Sci 68:9-17. 2002
    ....
  23. doi request reprint 2012 Global Summit on Regulatory Science (GSRS-2012)--modernizing toxicology
    Margaret A Miller
    National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas 72079, USA
    Toxicol Sci 131:9-12. 2013
    ....
  24. doi request reprint Mechanistic toxicity evaluation of uncoated and PEGylated single-walled carbon nanotubes in neuronal PC12 cells
    Yongbin Zhang
    National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, Arkansas 72079, USA
    ACS Nano 5:7020-33. 2011
    ..These findings suggest that surface functionalization of SWCNTs decreases ROS-mediated toxicological response in vitro...
  25. ncbi request reprint Systems biology/systems toxicology: application to developmental neurotoxicology/neuroprotection
    William Slikker
    Division of Neurotoxicology, National Center for Toxicological Research FDA, 3900 NCTR Road, Jefferson, Arkansas 72079, USA
    Ann N Y Acad Sci 1053:309-10. 2005
  26. ncbi request reprint Application of a systems biology approach to developmental neurotoxicology
    William Slikker
    Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 9502, USA
    Reprod Toxicol 19:305-19. 2005
    ....
  27. doi request reprint The genetic toxicology of methylphenidate hydrochloride in non-human primates
    Suzanne M Morris
    Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States
    Mutat Res 673:59-66. 2009
    ..3 microg/ml. No significant increases in the frequencies of MN-RETs, HPRT mutants, or chromosome aberrations were detected in the treated animals compared to the control animals over the 20-month exposure period...
  28. doi request reprint Evaluation of mutagenic mode of action in Big Blue mice fed methylphenidate for 24 weeks
    Mugimane G Manjanatha
    Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research NCTR, US Food and Drug Administration, Jefferson, AR 72079, United States
    Mutat Res 680:43-8. 2009
    ..These results suggest that MPH is not mutagenic in mice and that the induction of tumors as previously reported in the liver is probably through a nongenotoxic mode of action...
  29. ncbi request reprint Improving predictive modeling in pediatric drug development: pharmacokinetics, pharmacodynamics, and mechanistic modeling
    William Slikker
    Office of Research, National Center for Toxicological Research FDA, 3900 NCTR Road, Jefferson, Arkansas 72079 9502, USA
    Ann N Y Acad Sci 1053:505-18. 2005
    ..Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human...
  30. ncbi request reprint Neuroimaging: new approaches for neurotoxicology
    Amy Pogge
    Division of Neurotoxicology, National Center for Toxicology Research, 3900 NCTR Road, Jefferson, AR 72079 9502, USA
    Neurotoxicology 25:525-31. 2004
    ..In addition, as these technologies have been primarily developed for clinical purposes, they provide an outstanding opportunity for cross-species and animal-to-human extrapolation and testing...
  31. pmc A microarray study of MPP+-treated PC12 Cells: Mechanisms of toxicity (MOT) analysis using bioinformatics tools
    Zengjun Xu
    Division of Neurotoxicology, National Center for Toxicological Research, U S Food and Drug Administration, 3900 NCTR Road, Jefferson, Arkansas 72079, USA
    BMC Bioinformatics 6:S8. 2005
    ..MPP+ depletes dopamine content and elicits cell death in PC12 cells. However, the mechanism of MPP+-induced neurotoxicity is still unclear...
  32. doi request reprint Silver nanoparticle induced blood-brain barrier inflammation and increased permeability in primary rat brain microvessel endothelial cells
    William J Trickler
    Neurochemistry Laboratory, Division of Neurotoxicology, National Center of Toxicological Research Food and Drug Administration, Jefferson, Arkansas 72079, USA
    Toxicol Sci 118:160-70. 2010
    ..Further, this study suggests that Ag-NPs may interact with the cerebral microvasculature producing a proinflammatory cascade, if left unchecked; these events may further induce brain inflammation and neurotoxicity...
  33. doi request reprint In silico drug repositioning: what we need to know
    Zhichao Liu
    ICF International at FDA National Center for Toxicological Research, Jefferson, AR 72079, USA
    Drug Discov Today 18:110-5. 2013
    ....
  34. ncbi request reprint Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations
    John F Bowyer
    Division of Neurotoxicology and Biometry and Risk Assessment, National Center for Toxicological Research FDA, 72079 9502, Jefferson, AR, USA
    Neurotoxicology 24:379-90. 2003
    ..There were 80% reductions in the plasma membrane-associated 5-HT transporters 6 months after either the FEN or MDMA dosing regimen indicating that both treatments produced long-term serotonergic effects...
  35. ncbi request reprint Sex differences in cytochrome P450 1B1, an estrogen-metabolizing enzyme, in the rhesus monkey telencephalon
    Andrew C Scallet
    Division of Neurotoxicology, National Center for Toxicological Research, NCTR FDA, 3900 NCTR Drive, Jefferson, AR 72079, USA
    J Chem Neuroanat 29:71-80. 2005
    ..These results suggest that CYP1B1 may subserve widespread metabolic functions in the female primate brain but have more restricted actions within the hippocampal pyramidal neurons of the male...
  36. ncbi request reprint Biomarkers of adult and developmental neurotoxicity
    William Slikker
    Division of Neurotoxicology, National Center for Toxicological Research FDA, HFT 132, 3900 NCTR Road, Jefferson, AR 72079 9502, USA
    Toxicol Appl Pharmacol 206:255-60. 2005
    ....
  37. doi request reprint Flow cytometric analysis of micronuclei in peripheral blood reticulocytes IV: an index of chromosomal damage in the rhesus monkey (Macaca mulatta)
    Charlotte E Hotchkiss
    The Bionetics Corporation, Jefferson, Arkansas 72079, USA
    Toxicol Sci 102:352-8. 2008
    ..Microscopy-based scoring is challenging due to the low frequency of RETs and MN-RET in monkeys, but sufficient numbers of cells are easily scored with the flow cytometric procedure...
  38. ncbi request reprint Neuroimaging: strategies to illuminate environment-disease linkages. Session II. Summary and research needs
    William Slikker
    Division of Neurotoxicology, National Center for Toxicological Research FDA, 3900 NCTR Road, Jefferson, AR 72079, USA
    Neurotoxicology 25:501-2. 2004
  39. ncbi request reprint The differential JunB responses to inhibition of succinate dehydrogenase in rat hippocampus and liver
    Beata D Przybyla-Zawislak
    Division of Neurotoxicology, FDA National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079 9502, USA
    Neurosci Lett 381:354-7. 2005
    ..In conclusion, out of the three ITFs transcripts examined here junb may activate different pathways depending on the tissue as indicated by differential responses to mitochondrial inhibition in the hippocampus and liver...
  40. ncbi request reprint Neuroprotection or neurotoxicity: impact of discontinuous dose-response curves on risk assessment
    William Slikker
    Division of Neurotoxicology, National Center for Toxicological Research FDA, Jefferson, Arkansas 72079, USA
    Ann N Y Acad Sci 993:158; discussion 159-60. 2003
  41. ncbi request reprint Adaptation to repeated cocaine administration in rats
    Zbigniew K Binienda
    Division of Neurotoxicology, NCTR FDA, Jefferson, Arkansas 72029, USA
    Ann N Y Acad Sci 965:172-9. 2002
    ..Further studies are necessary to establish whether regional alterations in blood flow and metabolic activity may underlie such observations...
  42. ncbi request reprint Dose-dependent transitions in mechanisms of toxicity
    William Slikker
    US FDA National Center for Toxicological Research, Jefferson, AR 72079, USA
    Toxicol Appl Pharmacol 201:203-25. 2004
    ..This paper addresses the issues discussed at both workshops, and presents the consensus conclusions drawn by expert participants...
  43. ncbi request reprint Behavioral test methods workshop
    William Slikker
    National Center for Toxicological Research FDA, Division of Neurotoxicology, 3900 NCTR Rd Jefferson 72079, United States
    Neurotoxicol Teratol 27:417-27. 2005
    ....
  44. ncbi request reprint Application of proteomics to the study of molecular mechanisms in neurotoxicology
    Richard M LoPachin
    Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Moses 7, 111 E, 210th St, Bronx, NY 10467, USA
    Neurotoxicology 24:761-75. 2003
    ....
  45. ncbi request reprint Maternal smoking during pregnancy and childhood obesity
    Rudiger Von Kries
    Institute of Social Pediatrics and Adolescent Medicine, Ludwig Maximilian University of Munich, Munich, Germany
    Am J Epidemiol 156:954-61. 2002
    ....
  46. ncbi request reprint Concern over decreased training in embryology and developmental/reproductive toxicology
    Gary Kimmel
    Birth Defects Res B Dev Reprod Toxicol 71:191-2. 2004
  47. ncbi request reprint Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors
    S J James
    Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children s Hospital Research Institute, Little Rock, AR 72202, USA
    Neurotoxicology 26:1-8. 2005
    ..The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations...
  48. ncbi request reprint Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data
    Jennifer Seed
    US Environmental Protection Agency, Washington, DC, USA
    Crit Rev Toxicol 35:664-72. 2005
    ....
  49. ncbi request reprint N-ethyl-N-nitrosourea (ENU) increased brain mutations in prenatal and neonatal mice but not in the adults
    William Slikker
    College of Letters and Science, University of California, Los Angeles 90024, USA
    Toxicol Sci 81:112-20. 2004
    ..These results demonstrate a differential mutagenic effect of ENU on the mouse brain depending on the stages of development and suggest an enhanced susceptibility of brain cancer hazard for perinatal exposure to genotoxicants...
  50. pmc Regional societies: fostering competitive research through virtual infrastructures
    Steven F Jennings
    Department of Applied Science at the University of Arkansas at Little Rock, USA
    PLoS Biol 2:e372. 2004
  51. ncbi request reprint Methylphenidate and chromosome damage
    David Jacobson-Kram
    Cancer Lett 260:216-8. 2008
  52. pmc Incorporating children's toxicokinetics into a risk framework
    Gary Ginsberg
    Connecticut Department of Public Health, Hartford, Connecticut 06134, USA
    Environ Health Perspect 112:272-83. 2004
    ..This type of resource information is intended to help the assessor begin to address the issues raised in this paper...
  53. ncbi request reprint Neurobehavioral assessment: a survey of use and value in safety assessment studies
    Lawrence D Middaugh
    Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Toxicol Sci 76:250-61. 2003
    ..The survey results emphasize the need for further research into the methods of behavioral assessment as well as the mechanisms underlying the neurobehavioral alterations...
  54. ncbi request reprint Sex-selective hippocampal alterations after adolescent nicotine administration: effects on neurospecific proteins
    Zengjun Xu
    Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
    Nicotine Tob Res 5:955-60. 2003
    ..We conclude that administration of nicotine to adolescent rats alters neuroproteins in the female hippocampus during withdrawal, effects that could contribute to neurobehavioral deficits...
  55. ncbi request reprint Role of the standard deviation in the estimation of benchmark doses with continuous data
    David W Gaylor
    Gaylor and Associates, LLC, Little Rock, AR, USA
    Risk Anal 24:1683-7. 2004
    ..The bias increases as s(m) increases relative to s(a). The bias is relatively small if s(m) is less than one-third of s(a), a condition achieved in most experimental designs...