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Biomedical subjects

E H Cook

Publications and source records attributed to E H Cook.

At least 73 records · Page 4Linked to original sources
PubMed1997

Platelet serotonin measures in adolescents with conduct disorder.

Dysregulation of serotonergic function has been associated with aggression in several studies involving children, adolescents, and adults. This study investigated the relationship of platelet serotonergic measures to conduct disorder type, severity of aggression, and social skills impairment. Standardized assessments of diagnosis, aggression, impulsivity, and social skills were obtained from 43 male adolescents (ages 13-17) incarcerated at an involuntary residential treatment facility for juvenile offenders. Blood samples were collected and assayed for whole blood serotonin (5-HT) and platelet [3H]-paroxetine-labeled 5-HT-transporter binding. Whole blood 5-HT was higher in adolescents with conduct disorder, childhood type than in subjects with conduct disorder, adolescent type. Whole blood 5-HT was positively correlated with violence rating of the current offense and total offense points, and staff ratings of social skills impairment. Our findings are consistent with a relationship between 5-HT dysregulation and aggressive behavior in incarcerated adolescent boys with conduct disorder, particularly of childhood onset.

Adolescent↗
PubMed1997

Evidence of linkage between the serotonin transporter and autistic disorder.

The serotonin transporter gene (HTT) is a primary candidate in autistic disorder based on efficacy of potent serotonin transporter inhibitors in reducing rituals and routines. We initiated a candidate gene study of HTT in trios consisting of probands with autistic disorder and both parents. Preliminary transmission/disequilibrium test (TDT) analysis with 86 families revealed no evidence for linkage or linkage disequilibrium between autistic disorder and a polymorphism in the second intron of HTT. However, preferential transmission of a short variant of the HTT promoter was found in the same 86 trios (TDT chi 2 = 4.69, 1 d.f., P = 0.030). In further analyses, we considered haplotypes of the HTT promoter variant and second intron locus as alleles in a multiallelic TDT. Results confirmed the significance of the effect of this region (TDT chi 2 = 11.85, 4 d.f., P = 0.018). This provides preliminary evidence of linkage and association between HTT and autistic disorder.

Adolescent↗
PubMed1997

Autism or atypical autism in maternally but not paternally derived proximal 15q duplication.

Duplications of proximal 15q have been found in individuals with autistic disorder (AD) and varying degrees of mental retardation. Often these abnormalities take the form of a supernumerary inverted duplicated chromosome 15, more properly described as an isodicentric chromosome 15, or idic(15). However, intrachromosomal duplications also have been reported. In a few cases, unaffected mothers, as well as their affected children, carry the same duplications. During the course of the genotyping of trios of affected probands with AD and their parents, at the positional candidate locus D15S122, an intrachromosomal duplication of proximal 15q was detected by microsatellite analysis in a phenotypically normal mother. Microsatellite and methylation analyses of the pedigree in the following report show that, among three children, the two with autism or atypical autism have maternal inheritance of a 15q11-q13 duplication whereas the third child, who is unaffected, did not inherit this duplication. Their mother's 15q11-q13 duplication arose de novo from her father's chromosomes 15. This finding documents, for the first time, the significance of parental origin for duplications of 15q11-q13. In this family, paternal inheritance leads to a normal phenotype, and maternal inheritance leads to autism or atypical autism.

Aneuploidy↗
PubMed1996

The serotonin system in autism.

The serotonin system has been implicated as a factor in some cases of autism since the finding in 1961 of elevated serotonin (5-hydroxytryptamine) levels in the blood of patients with autism. This has been clarified as elevation in the platelet content of serotonin. Subjects with elevated whole blood serotonin levels have been shown to have elevated platelet serotonin transport into platelets and decreased serotonin 5-HT2 receptor binding. Most individuals with autism who are treated with potent serotonin transporter inhibitors have a reduction in ritualistic behavior and aggression. Reduction of central nervous system serotonin, induced by acute tryptophan depletion, causes a worsening of stereotyped behavior. Recent developments in the molecular biology of serotonin receptors are reviewed.

Autistic Disorder↗
PubMed1995

Attention deficit hyperactivity disorder and whole-blood serotonin levels: effects of comorbidity.

Whole-blood serotonin (5-hydroxytryptamine, 5-HT) levels were measured in children with attention deficit hyperactivity disorder (ADHD) with and without comorbid conduct disorder (CD) or oppositional-defiant disorder (ODD). It was hypothesized that the whole-blood 5-HT levels of ADHD probands would be significantly correlated with the whole-blood 5-HT levels of their mothers. Fifty-two children who met DSM-III-R criteria for ADHD were selected consecutively from an ADHD clinic (47 males--35 Caucasians, 10 African-Americans, and 2 Hispanics; 10 females--all Caucasians). Whole-blood 5-HT was assayed by high performance liquid chromatography and compared between ADHD children with and without comorbid CD or ODD. The familiality of whole-blood 5-HT levels was studied by Spearman's rank-order correlation. There were no significant age, race, or sex effects. There was no significant difference in whole-blood 5-HT levels between children with ADHD only (n = 22; 190 +/- 45 ng/ml) and ADHD with CD or ODD (n = 30; 212 +/- 67). However, 7 out of 30 (23%) children with ADHD+CD/ODD had whole-blood 5-HT levels > 270 ng/ml, while none of the ADHD-only children had whole-blood 5-HT levels > 270 ng/ml, a statistically significant difference. Whole-blood 5-HT levels showed significant positive correlations between 36 children with disruptive behavior disorders and their biological mothers (rs = 0.47). There was no difference in mean levels of whole-blood 5-HT between subgroups of children with ADHD with or without comorbid CD or ODD.(ABSTRACT TRUNCATED AT 250 WORDS)

Attention Deficit Disorder with Hyperactivity↗
PubMed1995

Association of attention-deficit disorder and the dopamine transporter gene.

Attention-deficit hyperactivity disorder (ADHD) has been shown to be familial and heritable, in previous studies. As with most psychiatric disorders, examination of pedigrees has not revealed a consistent Mendelian mode of transmission. The response of ADHD patients to medications that inhibit the dopamine transporter, including methylphenidate, amphetamine, pemoline, and bupropion, led us to consider the dopamine transporter as a primary candidate gene for ADHD. To avoid effects of population stratification and to avoid the problem of classification of relatives with other psychiatric disorders as affected or unaffected, we used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the dopamine transporter locus (DAT1) and DSM-III-R-diagnosed ADHD (N = 49) and undifferentiated attention-deficit disorder (UADD) (N = 8) in trios composed of father, mother, and affected offspring. HHRR analysis revealed significant association between ADHD/UADD and the 480-bp DAT1 allele (chi 2 7.51, 1 df, P = .006). When cases of UADD were dropped from the analysis, similar results were found (Chi 2 7.29, 1 df, P = .007). If these findings are replicated, molecular analysis of the dopamine transporter gene may identify mutations that increase susceptibility to ADHD/UADD. Biochemical analysis of such mutations may lead to development of more effective therapeutic interventions.

Adolescent↗
PubMed1994

Fluoxetine effects on cerebral glucose metabolism.

In a counterbalanced, double-blind, placebo-controlled trial, 40 mg of fluoxetine was administered to four healthy adult volunteers (three men, one woman; age range 20-39 years), 90 min before injection of 6-7.5 mCi of [18F]-2-deoxyglucose to measure cerebral metabolic rate of glucose (CMRglu). Subjects were engaged in a visual monitoring task shortly before and during scanning with a PETT-VI tomograph. Global CMRglu did not differ when placebo (8.93 +/- 0.96 mg 100 g-1 min-1) was compared to fluoxetine (8.22 +/- 0.86 mg 100 g-1 min-1; paired t-test = 0.82, df = 3, p < 0.48). However, statistical parametric mapping of differences in CMRglu between placebo and fluoxetine conditions revealed regional effects of fluoxetine shown by decreased metabolism in the amygdaloid complex, hippocampal formation and ventral striatum, and by increased metabolism centered in the right superior parietal lobe (Brodmann area 7). Parametric mapping for use in PET studies of glucose metabolism represents a significant new tool for studying drug effects in humans.

Adult↗
PubMed1994

Depressive and obsessive-compulsive symptoms in hyperserotonemic parents of children with autistic disorder.

Because of previous findings that parents of children with autistic disorder may be at increased risk for anxiety disorders and/or mood disorders, the Center for Epidemiological Studies-Depression (CES-D) Scale and the Modified Maudsley Obsessive-Compulsive Inventory (MMOCI) were administered to parents of children with autistic disorder and parents of children with Down's syndrome. Parents with normal whole blood serotonin levels who had children with autistic disorder and parents of children with Down's syndrome had significantly lower CES-D depression scores than parents with elevated whole blood serotonin levels who had children with autistic disorder. Hyperserotonemic parents of children with autistic disorder had significantly higher MMOCI scores than parents of children with Down's syndrome.

Adult↗
PubMed1994

Primary structure of the human platelet serotonin 5-HT2A receptor: identify with frontal cortex serotonin 5-HT2A receptor.

Previous radioligand binding studies have demonstrated human platelet serotonin2A (5-HT2A) receptor binding sites. Pharmacological similarities between platelet and frontal cortex 5-HT2A receptor binding parameters have been demonstrated. However, it is not clear whether the platelet 5-HT2A receptor primary structure is identical to that of the brain receptor. Three overlapping cDNAs were obtained to span completely the coding region of the 5-HT2A receptor. These clones were sequenced with external and internal primers. The nucleotide sequence of human platelet 5-HT2A cDNA was identical to that reported for the human frontal cortex 5-HT2A receptor, except for nucleotide 102 (T-->C), which has been reported to represent a normal DNA polymorphism that does not alter the amino acid sequence. This finding may have implications in the study of neuropsychiatric disorders for which altered platelet 5-HT2A receptor binding has been demonstrated.

Adult↗
PubMed1993

Receptor inhibition by immunoglobulins: specific inhibition by autistic children, their relatives, and control subjects.

Forty-two parents of children with autistic disorder, 15 children with autistic disorder, 17 siblings of children with autistic disorder, and 12 unrelated normal adult controls were studied to determine if immunoglobulins isolated from their plasma would inhibit binding of the 5HT1A agonist, [3H]-8-hydroxy-N,N-dipropyl-2-aminotetralin (DPAT) to 5HT1A receptors in human hippocampal membranes. There were no significant differences among the means of percentage inhibition of DPAT binding of parents, children with autistic disorder, siblings, or unrelated controls. In addition, there were no differences in the proportion of subjects with > 15% DPAT inhibition among autistic children, their parents, their siblings, or unrelated controls. Immunoglobulin inhibition was not specific for the 5HT1A receptor binding site, since immunoglobulins inhibited binding to 5HT2, D1, D2, and alpha 2-adrenergic binding sites. The immunoglobulins isolated from normal controls inhibited [3H]-rauwolscine binding at alpha 2-adrenergic sites less than immunoglobulins of children with autistic disorder and their parents and siblings. This study did not support the hypothesis that autoantibodies to 5HT1A or 5HT2 receptors are characteristic of autistic disorder.

Adolescent↗
PubMed1993

Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder.

Platelet serotonin (5-HT) studies were conducted with 12 hyperserotonemic and 12 normoserotonemic age-, sex-, and relationship-matched relatives of autistic probands. Each group consisted of 7 mothers, 4 fathers, and 1 sister of autistic children and adolescents. The density (Bmax) of platelet 5-HT2 receptor binding sites, labelled with [3H]-lysergic acid diethylamide (LSD), was significantly lower in 11 hyperserotonemic subjects compared to 12 normoserotonemic subjects (40.9 +/- 13.5 fmol/mg protein, 59.6 +/- 13.2; p < 0.004). The affinity (Kd) for [3H]-LSD binding did not differ. Although the density (Bmax) of [3H]-paroxetine binding did not differ between groups, there was a small difference in the affinity (Kd) for [3H]-paroxetine binding (hyperserotonemic 47.6 +/- 9.0 pM, normoserotonemic 54.8 +/- 12.1; p < 0.05). There were no significant differences in platelet 5-HT uptake, or in thrombin-stimulated 5-HT release. Basal, 5-HT-stimulated, and arginine-vasopressin (AVP)-stimulated inositol phosphate production, as well as basal, prostaglandin E1 (PGE1)-, and forskolin-stimulated cAMP production did not differ. There were significant correlations between whole blood 5-HT levels and LSD Bmax (rs = -0.63, N = 23, p < 0.002) and whole blood 5-HT levels and 5-HT uptake Vmax (rs = 0.56, N = 18, p < 0.02). However, [3H]-LSD labelled 5-HT2 binding and 5-HT uptake were not correlated with each other. Hyperserotonemia of autism may be heterogeneous with one subgroup of subjects with increased 5-HT uptake and another subgroup with decreased 5-HT2 binding.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Autistic disorder and post-traumatic stress disorder.

The present case study examined an adolescent boy who initially was evaluated at our clinic and was found to meet DSM-III-R criteria for autistic disorder. After placement in a residential school using Daily Life Therapy for autistic disorder, the subject reported being physically abused by a staff member. Additional psychiatric evaluation revealed post-traumatic stress disorder (PTSD) including symbolic anxiety and repetition of the trauma. The diagnosis of PTSD should be considered in children with autistic disorder and other severe developmental disorders who have experienced physical and sexual abuse. Furthermore, parents, professionals, educators, and child care workers struggle with emotional reactions to children with severe developmental disorders and may have difficulty accepting the reality of the child rather than the fantasy of the "wished-for child." The disappointment of this fantasy and the equating of the child's weaknesses as one's own may lead to personal devaluation and increase the risk of abusive behavior.

Autistic Disorder↗
PubMed1993

Clinical and neurochemical effects of fenfluramine in children with autism.

Fifteen children with autism were treated with 60 mg d,l-fenfluramine (FEN) or placebo in a double-blind A-B-A protocol followed immediately by double-blind placebo-controlled crossover administration of FEN (total duration 62 weeks). Both biochemical and clinical outcomes were examined. Biochemically, FEN led to an increase in dihydroxyphenylacetic acid (DOPAC) and decreases in whole-blood serotonin (5-HT), plasma norepinephrine (NE), and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG). The decrease in whole-blood 5-HT was seen only during treatment with FEN. However, NE levels did not return to baseline as long as 8 weeks after the first FEN treatment period. Increases in DOPAC were greater during the second FEN treatment period than the first. Persistent changes in catecholamine regulation may be related to previously reported long-term effects on central nervous system 5-HT after FEN. Clinically, FEN led to a modest decrease in parent, but not teacher, ratings of hyperactivity and to a small reduction in sensorimotor abnormalities. Abnormal social and affectual responses also decreased, but this was not directly related to FEN treatment. Effects on cognition were equivocal. Hyperserotonemic subjects did not differ from normoserotonemic subjects in clinical response. Overall, no significant advantage for the use of FEN could be established.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Fluoxetine treatment of children and adults with autistic disorder and mental retardation.

An open trial of pharmacological treatment with fluoxetine, ranging from 20 mg every other day to 80 mg per day, led to a significant improvement in Clinical Global Impressions ratings of Clinical Severity in 15 of 23 subjects with autistic disorder and 10 of 16 subjects with mental retardation. Six of 23 patients with autistic disorder and 3 of 16 patients with mental retardation had side effects which significantly interfered with function, consisting predominantly of restlessness, hyperactivity, agitation, decreased appetite, or insomnia. Double-blind studies of the efficacy of pharmacological agents that potently inhibit 5-HT uptake in the treatment of mental retardation coexisting with Axis I psychiatric disorders (especially obsessive-compulsive disorder) and autistic disorder are warranted.

Adolescent↗