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1.  A cluster randomized control field trial of the ABRACADABRA web-based reading technology: replication and extension of basic findings 
Frontiers in Psychology  2014;5:1413.
The present paper reports a cluster randomized control trial evaluation of teaching using ABRACADABRA (ABRA), an evidence-based and web-based literacy intervention ( with 107 kindergarten and 96 grade 1 children in 24 classes (12 intervention 12 control classes) from all 12 elementary schools in one school district in Canada. Children in the intervention condition received 10–12 h of whole class instruction using ABRA between pre- and post-test. Hierarchical linear modeling of post-test results showed significant gains in letter-sound knowledge for intervention classrooms over control classrooms. In addition, medium effect sizes were evident for three of five outcome measures favoring the intervention: letter-sound knowledge (d= +0.66), phonological blending (d = +0.52), and word reading (d = +0.52), over effect sizes for regular teaching. It is concluded that regular teaching with ABRA technology adds significantly to literacy in the early elementary years.
PMCID: PMC4255498  PMID: 25538663
randomized controlled trial; reading development; web applications; internet; intervention; elementary school education
2.  Spatial and Temporal Mapping of De novo Mutations in Schizophrenia To a Fetal Prefrontal Cortical Network 
Cell  2013;154(3):518-529.
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia, then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional co-expression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
PMCID: PMC3894107  PMID: 23911319
3.  Insights into bilaterian evolution from three spiralian genomes 
Nature  2012;493(7433):526-531.
Current genomic perspectives on animal diversity neglect two prominent phyla, the molluscs and annelids, that together account for nearly one-third of known marine species and are important both ecologically and as experimental systems in classical embryology1–3. Here we describe the draft genomes of the owl limpet (Lottia gigantea), a marine polychaete (Capitella teleta) and a freshwater leech (Helobdella robusta), and compare them with other animal genomes to investigate the origin and diversification of bilaterians from a genomic perspective. We find that the genome organization, gene structure and functional content of these species are more similar to those of some invertebrate deuterostome genomes (for example, amphioxus and sea urchin) than those of other protostomes that have been sequenced to date (flies, nematodes and flatworms). The conservation of these genomic features enables us to expand the inventory of genes present in the last common bilaterian ancestor, establish the tripartite diversification of bilaterians using multiple genomic characteristics and identify ancient conserved long- and short-range genetic linkages across metazoans. Superimposed on this broadly conserved pan-bilaterian background we find examples of lineage-specific genome evolution, including varying rates of rearrangement, intron gain and loss, expansions and contractions of gene families, and the evolution of clade-specific genes that produce the unique content of each genome.
PMCID: PMC4085046  PMID: 23254933
4.  Evaluation of HLA Polymorphisms in Relation to Schizophrenia Risk and Infectious Exposure 
Schizophrenia Bulletin  2012;38(6):1149-1154.
Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. Method: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. Results: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. Conclusions: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.
PMCID: PMC3494045  PMID: 22966150
HLA; gene; HSV-1; cytomegalovirus; schizophrenia; African American; kwd>
5.  Principal Components of Heritability From Neurocognitive Domains Differ Between Families With Schizophrenia and Control Subjects 
Schizophrenia Bulletin  2012;39(2):464-471.
Objective: Various measures of neurocognitive function show mean differences among individuals with schizophrenia (SZ), their relatives, and population controls. We use eigenvector transformations that maximize heritability of multiple neurocognitive measures, namely principal components of heritability (PCH), and evaluate how they distribute in SZ families and controls. Methods: African-Americans with SZ or schizoaffective disorder (SZA) (n = 514), their relatives (n = 1092), and adult controls (n = 300) completed diagnostic interviews and computerized neurocognitive tests. PCH were estimated from 9 neurocognitive domains. Three PCH, PCH1–PCH3, were modeled to determine if status (SZ, relative, and control), other psychiatric covariates, and education were significant predictors of mean values. A small-scale linkage analysis was also conducted in a subset of the sample. Results: PCH1, PCH2, and PCH3 account for 72% of the genetic variance. PCH1 represents 8 of 9 neurocognitive domains, is most highly correlated with spatial processing and emotion recognition, and has unadjusted heritability of 68%. The means for PCH1 differ significantly among SZ, their relatives, and controls. PCH2, orthogonal to PCH1, is most closely correlated with working memory and has an unadjusted heritability of 45%. Mean PCH2 is different only between SZ families and controls. PCH3 apparently represents a heritable component of neurocognition similar across the 3 diagnostic groups. No significant linkage evidence to PCH1–PCH3 or individual neurocognitive measures was discovered. Conclusions: PCH1 is highly heritable and genetically correlated with SZ. It should prove useful in future genetic analyses. Mean PCH2 differentiates SZ families and controls but not SZ and unaffected family members.
PMCID: PMC3576168  PMID: 22234486
schizophrenia; cognition; heritability; principal components; linkage
6.  Christopher Smallwood Savage 
BMJ : British Medical Journal  2008;336(7642):513.
PMCID: PMC2258390
7.  Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples 
Recessive mutations in the Phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH “tag” SNPs and 3 exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414). The samples included two US Caucasian cohorts (260 trios, 230 independent cases, 474 controls), Bulgarian families (659 trios), and an African-American sample (464 families, 401 controls). Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele (G) of rs1522305 from case-control analyses (z = 2.99, p = 0.006). This SNP was independently replicated in the Bulgarian cohort (z = 2.39, p = 0.015). A non-significant trend was also observed among African-American families (z = 1.39, p = 0.165), and combined analyses of all four samples were significant (rs1522305: χ2 = 23.28, 8 d.f., p = 0.003). These results for this SNP met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case-control results in African-Americans detected an association with L321L (p = 0.047, OR = 1.46). Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted.
PMCID: PMC2738981  PMID: 18937293
8.  How Does This Happen? Part I: Mechanisms of Adverse Drug Reactions Associated with Psychotropic Medications 
To review the background and mechanisms behind how certain psychotropic medications cause adverse drug reactions.
A literature review pertaining to several interesting and unusual adverse drug reactions attributed to selected psychotropic medications was conducted. These include: 1) QTc interval prolongation secondary to ziprasidone, pimozide, and other antipsychotic agents. 2) Nephrogenic diabetes insipidus and hypernatremia secondary to lithium. 3) Hypothyroidism secondary to lithium. 4) Erectile dysfunction secondary to selective serotonin and serotonin/norepinephrine reuptake inhibitors (SSRIs/SNRIs).
Biochemical mechanisms of how certain psychotropic medications cause adverse drug reactions were reviewed. Specific interventions and monitoring recommendations to prevent or reduce the impact of these adverse reactions are discussed briefly.
Knowledge of risk factors and mechanisms of adverse drug reactions with psychotropic medications can help to guide medication prescribing, monitoring and interventions to prevent or mitigate these reactions.
PMCID: PMC2809445  PMID: 20119566
9.  Pathways to Long-Term Recovery: A Preliminary Investigation 
Journal of psychoactive drugs  2002;34(3):305-311.
Recovery from addiction is a lifelong process. While there is a large body of empirical data on the short-term effectiveness (1-2 years) of various treatment modalities, very little is known about the processes of recovery over time. This is particularly unfortunate as treatment gains are often short-lived and even multiple treatment episodes do not always succeed in breaking the addiction cycle. Further, treatment represents only one of the paths to recovery.
This paper reports on a study of individuals in long-term recovery from substance abuse (median = 12 years) and examines the factors they cite as important in establishing and maintaining their recovery status. Key factors reported were social and community support, affiliation with 12-step organizations and negative consequences of substance use. Implications for clinical practice and future research directions are discussed.
PMCID: PMC1852519  PMID: 12422942
Recovery; addiction; 12-step; substance abuse; abstinence
10.  Preschool foundations of early reading acquisition 
Paediatrics & Child Health  2006;11(9):589-593.
The present paper describes research on the skills and processes associated with word and text reading acquisition in preschool children and during the first years of school. The aim is to provide an overview that gives a sense of the important milestones in language and literacy acquisition. A comparison of children’s performances against these milestones may thus guide effective intervention for health professionals, parents and other professionals. Also summarized and explored are the role of speech perception and production, grammatical and syntactic skills, and metacognitive skills, including phonological awareness.
PMCID: PMC2528655  PMID: 19030330
Child development; Emergent literacy; Language development; Reading
11.  Financial Capacity in Persons with Schizophrenia and Serious Mental Illness: Clinical and Research Ethics Aspects 
Schizophrenia Bulletin  2005;32(1):81-91.
In contrast with issues of consent capacity, financial capacity has received surprisingly little clinical or ethical attention in the psychiatric literature. Issues of financial capacity emerge frequently regarding clients with serious mental illness (SMI), and their resolution has practical and ethical significance for clients, their families, and mental health professionals. These issues include whether a client has sufficient financial skills and judgment to live independently, whether a client requires a representative payee, and what goals for community reintegration should be established with a client. Similar to informed consent, issues of financial capacity raise ethical challenges for clinicians, caseworkers, and agencies. The present article addresses clinical and research ethics questions related to financial capacity in clients with schizophrenia and SMI. Clinical questions concern evaluation of financial capacity in clients with SMI, whether to seek assignment of a mandatory representative payee, whether to leverage treatment compliance through a representative payee arrangement, and whether a mental health professional should also serve as a client's representative payee. The research ethics question addresses implications of providing financial compensation for research participation to individuals with SMI and limited financial capacity and means. The ultimate goal of this article is to focus clinical and ethical attention on a neglected decisional capacity in SMI that is of fundamental importance for clients, families, clinicians, and researchers.
PMCID: PMC2632186  PMID: 16293810
financial capacity; ethics; schizophrenia; SMI; representative payee
12.  African-American community attitudes and perceptions toward schizophrenia and medical research: an exploratory study. 
INTRODUCTION: Ensuring adequate representation of all demographic groups in medical research is necessary in order to ensure that the benefits associated with participation are equitably shared. Mental health research is unique in that the stigma associated with mental illness, such as schizophrenia, further hinders participation. Using focus groups, we set out to explore the attitudes and views of African Americans with regard to schizophrenia and medical research. METHODS: Four focus group discussions were conducted, with 23 participants divided into two groups of working and retired adults, and two groups of full- and part-time students selected from inner-city residents of Birmingham, AL, and surrounding counties. Data obtained were analyzed using the content analysis method. RESULTS: Diverse views were expressed about the cause of mental illness, and much of this was influenced by cultural beliefs. There was considerable misunderstanding of schizophrenia, and the majority of participants described the disease in terms of positive symptoms only. Whereas for older participants the Tuskegee syphilis study experience was an important factor in their reluctance to participate in medical research, younger participants expressed no knowledge of the study. Among younger participants an assumed level of social distrust was evident, with prominent fear of participating in research that employs physically intrusive methods. CONCLUSION: The provision of accurate information through trusted community sources and open dialogue will help to dispel myths, correct faulty assumptions and increase African-American participation in schizophrenia research.
PMCID: PMC2594797  PMID: 16532974
13.  Loss of Matrix Adhesion Triggers Rapid Transformation-Selective Apoptosis in Fibroblasts  
The Journal of Cell Biology  1997;138(4):901-911.
Cell–matrix and cell–cell adhesion are recognized physiological determinants of cell growth and survival. In epithelial and endothelial cell systems, oncogenic transformation has in several cases been shown to confer resistance to apoptosis upon depriving cells of substrate adhesion. We examined the effects of oncogenic transformation in adherent versus adhesion- deprived primary embryonic fibroblasts. Whereas untransformed early passage fibroblasts undergo cell cycle arrest, their Myc/Ras- or E1A/Ras-transformed counterparts rapidly enter apoptosis when placed into suspension. This phenomenon also occurs upon incubation with a soluble, RGD-containing integrin ligand and is blocked by a peptide antagonist to ICE family proteases or by aggregation of cells plated at high density. Loss of wild-type p53 modulates the kinetics but does not abrogate this death pathway. Transformation with activated Src rather than Ras rendered fibroblasts selectively resistant to adhesion-dependent apoptosis, an effect likely related to Src's role in integrin signaling, while simultaneously sensitizing the cells to radiation-induced apoptosis. Thus cell adhesion events regulate transformation-selective apoptosis in fibroblasts and provide potentially important targets for understanding and interfering with tumor cell viability.
PMCID: PMC2138041  PMID: 9265655

Results 1-13 (13)