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Biomedical subjects

E H Cook

Publications and source records attributed to E H Cook.

At least 55 records · Page 3Linked to original sources
PubMed1999

Serotonin transporter gene (HTTLPR) is not in linkage disequilibrium with prepubertal and early adolescent bipolarity.

BACKGROUND: As part of an ongoing, larger study, "Phenomenology and Course of Pediatric Bipolarity", a subset of prepubertal and early adolescent onset bipolar (PEA-BP) probands, on whom trio blood collection was complete, were used to study genetic transmission of the serotonin transporter linked promoter region (HTTLPR) short and long alleles using the transmission disequilibrium test(TDT). The HTTLPR alleles were selected based on postulated serotonergic mechanisms for PEA-BP and on the burgeoning number of HTTLPR allele studies in bipolar (BP) adults. METHODS: There were 46 complete trios of PEA-BP probands and both biological parents. Probands had a mean age of 11.1 +/- 3.0 years and a mean age of onset of PEA-BP of 8.1 +/- 4.0 years. Comprehensive diagnostic assessments included a semi-structured research interview, the WASH-U-KSADS, administered separately to mothers and to children by blind raters. Probands manifested severe impairment (CGAS 43.9 +/- 8.9), elated mood (84.8%), grandiosity (78.3%), rapid cycling (78.3%) and psychosis (63.0%). The HTTLPR length variant was genotyped using fluorescently labeled primers and automated capillary electrophoresis using laser-induced fluorescence. RESULTS: The TDT was not significant (TDT chi square = .020, df = 1, p = .89). CONCLUSIONS: This negative result is consistent with the one negative TDT and two negative linkage studies of HTTLPR alleles in bipolar adults in the literature.

Adolescent↗
PubMed1999

Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. American Academy of Child and Adolescent Psychiatry Working Group on Quality Issues.

Autism and the related pervasive developmental disorders are characterized by patterns of delay and deviance in the development of social, communicative, and cognitive skills, which arise in the first years of life. Although frequently associated with mental retardation, these conditions are distinctive in terms of their course and treatment. These conditions have a wide range of syndrome expression, and their management presents particular challenges for clinicians. Individuals with these conditions can present for clinical care at any point in development. The multiple developmental and behavioral problems associated with these conditions often require the care of multiple providers; coordination of services and advocacy for individuals and their families is important. Early, sustained intervention is indicated, as is the use of various treatment modalities (e.g., pharmacotherapy, special education, speech/communication therapy, and behavior modification).

Adolescent↗
PubMed1999

The screening and diagnosis of autistic spectrum disorders.

The Child Neurology Society and American Academy of Neurology recently proposed to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for their memberships. This endeavor was expanded to include representatives from nine professional organizations and four parent organizations, with liaisons from the National Institutes of Health. This document was written by this multidisciplinary Consensus Panel after systematic analysis of over 2,500 relevant scientific articles in the literature. The Panel concluded that appropriate diagnosis of autism requires a dual-level approach: (a) routine developmental surveillance, and (b) diagnosis and evaluation of autism. Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.

Asperger Syndrome↗
PubMed1999

Mutation screening of the UBE3A/E6-AP gene in autistic disorder.

Previous reports of individuals with autistic disorder with maternal duplications of 15q11-q13, the Prader-Willi/Angelman syndrome region, suggest this area as a source of candidate genes in autistic disorder. Maternal truncation mutations in UBE3A, which encodes for E6-AP ubiquitin-protein ligase, have been shown to cause Angelman syndrome, which can also result from the absence of maternal chromosomal material from this region. Despite showing no evidence for imprinting in other tissues, this gene was recently discovered to be preferentially maternally expressed in human brain and expressed solely from the murine maternal chromosome in the hippocampus and cerebellar Purkinje cells, regions implicated in the neuropathology of autism. Based on this evidence, the coding region and a putative promoter region were sequenced in ten autistic subjects. Several polymorphisms were detected, but no evidence was found for a functional mutation. Evidence for likely altered regulation of UBE3A expression in maternal 15q11-q13 duplications suggests further investigation of the regulatory regions of this gene in autistic disorder.

Autistic Disorder↗
PubMed1999

High throughput fluorescent CE-SSCP SNP genotyping.

Large numbers of single nucleotide polymorphisms (SNPs) are being identified by several laboratories for the purpose of developing dense genetic maps. Single-strand conformation polymorphism (SSCP) analysis has been widely used as a method for detecting novel sequence variations in PCR products. Differences in migration of single-stranded DNA can be used not only to find mutations, but to genotype SNPs in large sample populations. Using PCR with fluorescent labeling and automated capillary electrophoresis SSCP (CE-SSCP), we have developed a panel of 15 functional candidate SNPs. With an automated single capillary instrument, relatively rapid and low cost CE-SSCP SNP genotyping using currently available technology is feasible for 135 000 genotypes per year. With parallel multiple array capillary electrophoresis, more genotypes per year may be attainable.

Automation↗
PubMed1999

Anxiolytics, adrenergic agents, and naltrexone.

OBJECTIVE: To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (beta-blockers and alpha 2-adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research. METHOD: All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included. RESULTS: The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy. CONCLUSIONS: The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; beta-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.

Adolescent↗
PubMed1998

Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial.

CONTEXT: The serotonin reuptake inhibitors are the treatment of choice for patients with obsessive-compulsive disorder; however, empirical support for this assertion has been weaker for children and adolescents than for adults. OBJECTIVE: To evaluate the safety and efficacy of the selective serotonin reuptake inhibitor sertraline hydrochloride in children and adolescents with obsessive-compulsive disorder. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: One hundred eighty-seven patients: 107 children aged 6 to 12 years and 80 adolescents aged 13 to 17 years randomized to receive either sertraline (53 children, 39 adolescents) or placebo (54 children, 41 adolescents). SETTING: Twelve US academic and community clinics with experience conducting randomized controlled trials. INTERVENTION: Sertraline hydrochloride was titrated to a maximum of 200 mg/d during the first 4 weeks of double-blind therapy, after which patients continued to receive this dosage of medication for 8 more weeks. Control patients received placebo. MAIN OUTCOME MEASURES: The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH GOCS), and the NIMH Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) rating scales. RESULTS: In intent-to-treat analyses, patients treated with sertraline showed significantly greater improvement than did placebo-treated patients on the CY-BOCS (adjusted mean, -6.8vs -3.4, respectively; P=.005), the NIMH GOCS (-2.2 vs -1.3, respectively; P=.02), and the CGI-I (2.7 vs 3.3, respectively; P=.002) scales. Significant differences in efficacy between sertraline and placebo emerged at week 3 and persisted for the duration of the study. Based on CGI-I ratings at end point, 42% of patients receiving sertraline and 26% of patients receiving placebo were very much or much improved. Neither age nor sex predicted response to treatment. The incidence of insomnia, nausea, agitation, and tremor were significantly greater in patients receiving sertraline; 12 (13%) of 92 sertraline-treated patients and 3 (3.2%) of 95 placebo-treated patients discontinued prematurely because of adverse medical events (P=.02). No clinically meaningful abnormalities were apparent on vital sign determinations, laboratory findings, or electrocardiographic measurements. CONCLUSION: Sertraline appears to be a safe and effective short-term treatment for children and adolescents with obsessive-compulsive disorder.

Adolescent↗
PubMed1998

Scanning of the dopamine D1 and D5 receptor genes by REF in neuropsychiatric patients reveals a novel missense change at a highly conserved amino acid.

In previous analyses of schizophrenic patients, multiple missense changes and one nonsense change were identified in the D5 dopamine receptor (DRD5) gene, but no sequence changes of likely functional significance were identified in the D1 dopamine receptor (DRD1) gene. In the present study, we examined these genes in patients with certain other neuropsychiatric disorders that may be related to dopaminergic dysregulation. The coding regions of the DRD1 and DRD5 genes were examined in 25 and 25 autistic patients, 25 and 28 attention deficit hyperactivity disorder patients, and 51 and 43 alcoholic patients, respectively. In addition, the DRD5 gene was examined in 75 schizophrenic patients to search for additional variants affecting protein structure or expression (VAPSEs). These patients were analyzed with REF (restriction endonuclease fingerprinting), a hybrid between SSCP and restriction endonuclease digestion, which allows the entire coding sequence to be screened in one lane of a gel. Approximately 800 kb of genomic sequence were examined. No sequence changes were identified in the DRD1 gene among the 101 patient samples analyzed. Two sequence changes were identified in the DRD5 gene among the 171 patient samples. These included one previously identified silent polymorphism at base pair 978 (P326P). The change was identified in patients from all disease categories and from different ethnic backgrounds. One novel missense change, L88F, occurred in transmembrane domain II at a highly conserved amino acid in all dopamine receptors as well as in alpha1- and beta-adrenergic receptors. The mutation was identified in a Caucasian male patient with autism. Further analysis is necessary to determine if this missense change is associated with a particular neuropsychiatric phenotype.

Adult↗
PubMed1998

Brain dopamine transporter messenger RNA and binding sites in cocaine users: a postmortem study.

BACKGROUND: Results of recent radioligand binding experiments suggest that chronic cocaine exposure increases dopamine transporter (DAT) synthesis throughout the striatum of humans. However, detection of cocaine binding site increases in animals and humans has varied depending on the radioligand used. The present experiment tested the hypothesis in cocaine-using humans that synthesis of midbrain DAT messenger RNA increases parallel with increased striatal DAT binding sites. METHODS: Striatal and midbrain samples were collected during autopsy examination from human cocaine users (n = 34) and from age-, sex-, and race-matched control subjects (n = 36). Levels of DAT messenger RNA were quantified in the medial and lateral midbrain regions using in situ hybridization, and striatal DAT binding sites were assessed by quantitative autoradiography using the DAT-specific radioligand [3H]WIN 35428. RESULTS: Striatal DAT binding sites were markedly increased in cocaine users, but, paradoxically, medial DAT messenger RNA levels were decreased. CONCLUSION: Cocaine exposure has a marked effect on DAT function, but the mechanisms involved may be complex.

Adult↗
PubMed1998

Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder.

The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (l) and short (s) variants of the HTT promoter have different transcriptional efficiencies. HTT promoter genotype and blood 5-HT concentration were examined in 70 subjects from 20 families ascertained through children and adolescents with a DSM-III-R diagnosis of OCD. The HTT promoter variant had a significant effect on blood 5-HT content. Subjects with the l/l and l/s genotypes had significantly higher blood 5-HT levels than did those with the s/s genotype. There was a significant interaction between HTT promoter genotype and seasonal variation in blood 5-HT content, with significant seasonal differences in 5-HT occurring only in the subjects with the l/l genotype. Further studies of the regulation of HTT gene expression are indicated.

Adolescent↗
PubMed1998

Association of an X-chromosome dodecamer insertional variant allele with mental retardation.

Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<< 1% in non-iII males) having an increased prevalence in non-Fragile X males with mental retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-Fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P < 0.001) and treatment with antidepressants (P < 0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation.

Alleles↗
PubMed1998

Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers.

Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder.

Autistic Disorder↗
PubMed1998

Molecular screening for proximal 15q abnormalities in a mentally retarded population.

Paternal or maternal deletions in the 15q11.2-q13 region are known to result in Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Maternal duplications in 15q11.2-q13 have been found in patients with autism. A population of adults with moderate to profound mental retardation was studied to examine the usefulness of PCR based molecular methods in screening for proximal chromosome 15 abnormalities. Two hundred and eighty-five subjects were initially screened at five microsatellite markers with average heterozygosity values of 0.74 (range 0.54-0.82). Of these subjects, four had a single allele at all five loci, suggestive of a deletion or uniparental isodisomy. The four samples were further screened with additional markers located within 15q11.2-q13 as well as markers telomeric to this region. One subject had uniparental disomy (UPD) and three subjects had a deletion. To determine the parental origin of the 15q11-q13 region containing the single haplotype, samples were analysed with a newly developed methylation specific PCR technique at the SNRPN locus. Each of the four subjects showed presence of the paternal allele and absence of the maternal allele. All cases had a phenotype consistent with Angelman syndrome as expected for the level of mental retardation, but the subject with UPD was distinct from the other subjects with an absence of a history of seizures and presence of bilateral undescended testes and Parkinsonism. Although Angelman syndrome has an estimated population prevalence of 0.008%, at least 1.4% of the moderately to profoundly mentally retarded subjects screened were found to have Angelman syndrome.

Adult↗
PubMed1998

Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels.

OBJECTIVE: Earlier platelet and postmortem brain studies have found alterations in serotonin transporter function in ethanol-abusing human subjects. The present investigation tested the hypothesis that brain serotonin transporter function is altered in chronic users of ethanol and cocaine, which might be related to a common serotonin transporter promoter polymorphism. METHOD: Serotonin transporter binding sites, serotonin transporter mRNA levels, and serotonin transporter promoter variants were quantified in postmortem samples from a group of human subjects who had been ethanol users or cocaine users and then compared to those of a matched group of comparison subjects. Quantitative autoradiographic and in situ hybridization assays were performed in midbrain samples that contained the dorsal and median raphe nuclei (the location of serotonin cell bodies that innervate the forebrain). RESULTS: There was a significant overall cocaine-by-ethanol-by-genotype interaction. Dorsal raphe [125I]CIT binding to the serotonin transporter was lower in cocaine users than in comparison subjects. In addition, serotonin transporter binding and serotonin transporter mRNA levels varied significantly by genotype. It was also found that serotonin transporter binding in subjects with either the short or heterozygote genotype was significantly higher in the ethanol-user subjects. CONCLUSIONS: Serotonin transporter binding sites were regulated in a region-specific and substance-specific pattern, which was not simply a local response to functional blockade. Also, a reciprocal relationship appeared to exist between cocaine and ethanol effects in the dorsal raphe, which may have interesting clinical implications for dual-diagnosis patients. It is possible that serotonin transporter promoter genotype may play a complex role in chronic ethanol dependence.

Adult↗
PubMed1998

Overt behavior problems and serotonergic function in middle childhood among male and female offspring of alcoholic fathers.

A large body of literature indicates that the serotonergic system is involved in behavioral regulation, as evidenced by the inverse relationship between impulsive aggression and serotonergic function found in adult alcoholics and nonalcoholics. However, studies of this relationship among child and adolescent offspring of alcoholics (COAs) have not previously been done. This study examines the potentially parallel relationship between behavioral dysregulation and low serotonergic function in young COAs. The relationship is of potential interest as a phenotypic marker of biological vulnerability to aggressiveness, which itself has been hypothesized to be a risk factor for later antisocial alcoholism. The present work is part of an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by the fathers' alcoholism classification. We examined the relationship between overt behavior problems in middle childhood (mean age = 10.5 +/- 1.7 years) and whole blood serotonin (5-HT) in a subsample of the offspring (N = 32 boys and 12 girls). Using a Child Behavior Checklist (CBCL) index of behavioral undercontrol, we obtained results indicating that high total behavior problem (TBP) children had lower levels of whole blood 5-HT than did low-TBP children (p < 0.01). These results support the hypothesis that there is an inverse relationship between whole blood serotonin levels and behavior problems in young male and female COAs. A father's alcoholism status was not significantly related to his child's 5-HT level, i.e., the child's phenotypic expression of behavioral dysregulation was more reliably connected to serotonergic function than was paternal alcoholism.

Adolescent↗