Biomedical subjects

J A Frazier

Publications and source records attributed to J A Frazier.

At least 37 records · Page 2Linked to original sources

PubMed1996

Smooth pursuit eye movements in childhood-onset schizophrenia: comparison with attention-deficit hyperactivity disorder and normal controls.

Abnormalities of the smooth pursuit eye movements of adults with schizophrenia have been well described. We examined smooth pursuit eye movements in schizophrenic children, contrasting them with normal and attention-deficit hyperactivity disorder (ADHD) subjects, to determine whether there is continuity of eye movement dysfunction between childhood- and adult-onset forms of schizophrenia. Seventeen schizophrenic children with onset of illness by age 12, 18 ADHD children, and 22 normal children were studied while engaged in a smooth pursuit eye tracking task. Eye tracking variables were compared across the three groups. Schizophrenic children exhibited significantly greater smooth pursuit impairments than either normal or ADHD subjects. Within the schizophrenic group, there were no significant relationships between eye tracking variables and clinical variables, or ventricular/brain ratio. Childhood-onset schizophrenia is associated with a similar pattern of smooth pursuit abnormalities to that seen in later-onset schizophrenia.

Adolescent↗

PubMed1996

Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia.

BACKGROUND: Early-onset schizophrenia (first psychotic symptoms by age 12 years) has been the subject of a small number of studies, and its biological continuity with later-onset disorder has not been established. In this study quantitative anatomic brain magnetic resonance images of children and adolescents with early-onset schizophrenia were compared with those of matched controls. Brain abnormalities in childhood-onset schizophrenia were examined in relation to those reported for later-onset schizophrenics. METHODS: Anatomic brain magnetic resonance imaging scans were obtained for 21 patients (mean +/- SD age, 14.6 +/- 2.1 years; range, 10 to 18 years) with childhood-onset schizophrenia (13 males, eight females) and 33 age-, sex-, height-, and weight-matched normal controls. Quantitative measurements were obtained for the cerebrum, anterior frontal region, lateral ventricles, thalamus, caudate, putamen, and globus pallidus. RESULTS: Total cerebral volume and midsagittal thalamic area were smaller in the patients (analysis of variance, P = .002, and analysis of covariance, P = .03, respectively); the caudate, putamen, and globus pallidus were larger in the patients (analysis of covariance, P = .05, P = .007, and P < .001, respectively); and the lateral ventricles tended to be larger in the patients (analysis of covariance, P = .06). Globus pallidus enlargement correlated with neuroleptic exposure and with age of onset of psychosis. The magnitude of abnormalities compared with controls was similar to that reported in adult studies, although there was a trend toward relatively smaller cerebral volumes for the childhood-onset group compared with controls. CONCLUSION: Brain anatomic abnormalities in childhood-onset schizophrenia are similar to those reported for adult populations, indicating overall continuity between these rare childhood cases and the adult schizophrenia populations.

Adolescent↗

PubMed1996

Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison.

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia. METHODS: Twenty-one patients (mean [+/-SD] age, 14.0 +/- 2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [+/-SD] final dose, 176 +/- 149 mg/d), or haloperidol, (16 +/- 8 mg/d). RESULTS: Clozapine was superior to haloperidol on all measures of psychosis (P = .04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine. CONCLUSIONS: Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.

Adolescent↗

PubMed1996

Temporal lobe morphology in childhood-onset schizophrenia.

OBJECTIVE: Neurodevelopmental models of schizophrenia imply that a more severe early brain lesion may produce earlier onset of psychotic symptoms. The medial temporal lobes have been proposed as possible locations for such a lesion. The authors tested this hypothesis in a group of children and adolescents with childhood-onset schizophrenia who had severe, chronic symptoms and who were refractory to treatment with typical neuroleptics. METHOD: Anatomic brain magnetic resonance imaging scans were acquired with a 1.5-T scanner for 21 patients (mean age=14.6 years, SD=2.1) who had onset of schizophrenia by age 12 (mean age at onset=10.2, SD=1.5) and 41 normal children. Volumes of the temporal lobe, superior temporal gyrus, amygdala, and hippocampus were measured by manually outlining these structures on contiguous 2-mm thick coronal slices. RESULTS: Patients with childhood-onset schizophrenia had significantly smaller cerebral volumes. With no adjustment for brain volume, no diagnostic differences were observed for any temporal lobe structure. Unexpectedly, with adjustment for total cerebral volume, larger volumes of the superior temporal gyrus and its posterior segment and a trend toward larger temporal lobe volume emerged for the patients with schizophrenia. These patients lacked the normal (right-greater-than-left) hippocampal asymmetry. CONCLUSIONS: These findings do not indicate a more severe medial temporal lobe lesion as the basis of very early onset schizophrenia.

Adolescent↗

PubMed1996

Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment.

OBJECTIVE: The effect of clozapine on striatal morphology was examined in adolescents with childhood-onset schizophrenia. METHOD: Eight adolescent patients with onset of psychosis before age 12 and eight matched comparison subjects had initial and 2-year follow-up brain magnetic resonance imaging scans. Basal ganglia and lateral ventricle volumes were measured. The patients were on a clozapine regimen during the 2-year interim. RESULTS: Caudate volume was larger in the patients at the initial scanning, decreased in the patients between scans, and did not differ significantly between the patients and the comparison subjects at the second scanning. CONCLUSIONS: Caudate enlargement in patients with childhood-onset schizophrenia who are taking typical neuroleptics appears to be secondary to medication exposure. Rescanning to examine basal ganglia morphology is indicated for these patients when they are taking an atypical neuroleptic.

Adolescent↗

PubMed1995

Childhood-onset schizophrenia: the severity of premorbid course.

OBJECTIVE: To review the premorbid histories of 23 children meeting DSM-III-R criteria for schizophrenia with onset before age 12 years and to compare these with childhood data of later-onset schizophrenics. METHOD: Premorbid features up to 1 year before onset of first psychotic symptoms were rated from hospital and clinic records, clinical interviews, rating scales, and tests. RESULTS: In keeping with previous studies, specific developmental disabilities and transient early symptoms of autism, particularly motor stereotypies, were common. Comparison with the childhood of later-onset schizophrenics showed greater delay in language development, and more premorbid speech and language disorders, learning disorders, and disruptive behavior disorders. (Sixty percent had received or were estimated to meet criteria for one or more clinical diagnoses.) CONCLUSIONS: Childhood-onset schizophrenia may represent a more malignant form of the disorder, although selection and ascertainment bias cannot be ruled out. The presence of prepsychotic language difficulties focuses attention on the importance of early temporal and frontal lobe development; early transient motor stereotypies suggest developmental basal ganglia abnormalities and extend previous findings seen in the childhood of later-onset patients.

Adolescent↗

PubMed1994

Separation anxiety: the etiology of nondisjunction in flies and people.

Two new studies examine the recombinational history of human chromosomes that nondisjoin at the first meiotic division in females. Our analysis of these studies suggests two possible etiologies of nondisjunction in terms of well-understood properties of chromosome mechanics. For both the X chromosome and for chromosome 21, 60-70% of nondisjoined chromosomes are derived from chiasmate bivalents, many of which display unusual patterns of exchange. The patterns of exchange and nondisjunction observed for human chromosome 21 parallel those exhibited by a mutation in Drosophila that impairs spindle assembly and function. Based on these similarities, we propose that nondisjunction of chromosome 21 in human females results from an age-dependent loss of spindle-forming ability. The recombinational histories of nondisjoining human X chromosomes are quite different from those of chromosome 21, but rather parallel those obtained for spontaneous nondisjunction in Drosophila females. The data for X chromosome disjunction in both species can be explained by a model in which nondisjunction is the consequence of the age-dependent movement of transposable elements. According to this model, nondisjunction is explained as the consequence of the repair of transposon-induced breaks in the DNA. Both models provide reasonable alternatives to biologically implausible explanations such as the 'production line hypothesis'.

Animals↗

PubMed1994

Childhood-onset schizophrenia: an NIMH study in progress.

An ongoing study of the phenomenology, genetics, neuropsychology, physiology (eye tracking, autonomic responsivity), neuroimaging, biochemistry, and pharmacology of childhood-onset schizophrenia is described, and pilot data are presented for the first 22 subjects. Differentiation from autism "spectrum" disorders and other poorly defined, severe neurodevelopmental disorders is needed. Eye tracking and autonomic results are similar to patterns seen in later-onset schizophrenia and possibly more striking. Magnetic resonance imaging showed larger left frontal ventricular horn area for the schizophrenia subjects, larger left caudate, and lack of normal caudate asymmetry. Fluorodeoxyglucose positron emission tomography during an auditory continuous performance task revealed decreased right parietal/occipital glucose metabolic rate in the schizophrenia subjects, which may be secondary to poor attentional performance, and increased glucose metabolic rate in three left frontal regions, a left parietal region, and the right putamen. Clozapine has been effective and well tolerated in an open trial with 12 adolescents who responded poorly to typical neuroleptics; 16 subjects have been enrolled in a double-blind comparison of haloperidol and clozapine. Longitudinal study of this narrowly defined and possibly more homogeneous group of very early-onset schizophrenia subjects will be relevant to current neurodevelopmental theories addressing the role of puberty, progression of pathology, and continuity or discontinuity with later-onset schizophrenia.

Adolescent↗

PubMed1994

An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia.

OBJECTIVE: To review the response of 11 adolescents with childhood-onset schizophrenia to a 6-week open clozapine trial. METHOD: Eleven children meeting DSM-III-R criteria for schizophrenia had a 6-week open trial of clozapine (mean sixth week daily dose 370 mg). Behavioral ratings included the Brief Psychiatric Rating Scale and Children's Global Assessment Scale. RESULTS: More than half showed marked improvement in Brief Psychiatric Rating Scale ratings by 6 weeks of clozapine therapy compared to admission drug rating and compared to a systematic 6-week trial of haloperidol. CONCLUSIONS: This open trial indicates that clozapine may be a promising treatment for children and adolescents with schizophrenia who do not respond well to typical neuroleptics. A double-blind placebo-controlled study is ongoing.

Adolescent↗

PubMed1994

Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response.

BACKGROUND: Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia. METHOD: Eleven patients (9 boys, 2 girls; mean age = 14.1 +/- 2.1 years) received a 6-week blinded or open trial of clozapine. Five patients also received 6 weeks of blinded or open haloperidol. Doses were increased on an individual basis to a mean 6-week dose of 5.99 +/- 2.6 mg/kg/day for clozapine and 0.24 +/- 0.20 mg/kg/day for haloperidol. The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject. Weekly blood samples were obtained during therapy and assayed by high performance liquid chromatography. RESULTS: The mean clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6 haloperidol level was 23.0 ng/mL (range, 6.2-44.3 ng/mL). The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77% and 18%, respectively, of those of the parent compound. The mean ratio of haloperidol/reduced haloperidol was 4.48 (range, 0.76-8.76). Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients (correlation range, 0.26-0.96). Conversely, poor and inconsistent correlations between haloperidol concentrations and clinical effects were observed. No relationships were noted between clozapine or haloperidol dose and clinical effects. CONCLUSION: Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults. Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement.

Adolescent↗

PubMed1994

Effect of okadaic acid on utilization of lipoprotein-derived cholesteryl esters by rat steroidogenic cells.

This study examines various functional, biochemical, and structural changes in rat adrenocortical and ovarian granulosa cells that could account for the decline in lipoprotein-supported hormone production after cell treatment with the protein phosphatase inhibitor, okadaic acid. Although the steroidogenic pathway enzymes in these cells are not in themselves affected by okadaic acid, the intracellular transport of cholesterol to important cellular processing sites is defective. That is, okadaic acid does not interfere with the internalization of lipoprotein-derived cholesteryl esters, but the mitochondrial utilization of cholesterol obtained from intracellular cholesterol storage sites is 50% reduced as compared to control cells. Two-dimensional electrophoresis gels from okadaic acid-treated cells demonstrate a number of hyperphosphorylated proteins. Morphological examination of the affected cells reveal completely disrupted Golgi complexes with attendant structures, but otherwise the cells appear unchanged. The results suggest that some necessary sterol transport protein (or cofactor or associated membrane) is adversely phosphorylated by okadaic acid, and is rendered dysfunctional.

Animals↗

PubMed1992

Fractionation and antigenic characterization of organelles of Eimeria tenella sporozoites.

Sporozoites of Eimeria tenella were disrupted by sonication and subcellular fractions were separated by sucrose gradient ultracentrifugation. Fractions from gradients were characterized by electron microscopical appearance and their polypeptide and antigenic profiles determined by PAGE and Western blotting with antisera to sporozoites and 1st- and 2nd-generation merozoites. Fractions containing micronemes, rhoptries or membranes showed markedly different polypeptide content and antigenic reactivity. Microneme epitopes were strongly conserved between sporozoites and 2nd-generation merozoites whereas the majority of rhoptry epitopes and many membrane epitopes were sporozoite specific. The only polypeptide of sporozoites which was strongly recognized by antisera raised to 1st generation merozoites was a microneme antigen of molecular weight approximately 100 kDa.

Animals↗

PubMed1991

A novel subgroup of exogenous avian leukosis virus in chickens.

An avian leukosis virus with a wide host range belonging to a new subgroup for chickens was isolated from meat-type chicken lines. The virus, of which HPRS-103 strain is the prototype, was of low oncogenicity in chickens but appeared to behave like an exogenous leukosis virus. Neutralizing antibodies to the virus were found in three of five meat-type chicken lines, but not in seven layer lines. The virus and its Rous sarcoma virus pseudotype did not replicate in, or transform, mammalian cells.

Animals↗

PubMed1987