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Biomedical subjects

J F Leckman

Publications and source records attributed to J F Leckman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex.

Little is known about regionally specific signals that control the number of neuronal progenitor cells in vivo. We have previously shown that the germline mutation of the basic fibroblast growth factor (Fgf2) gene results in a reduction in the number of cortical neurons in the adult. We show here that Fgf2 is expressed in the pseudostratified ventricular epithelium (PVE) in a dorsoventral gradient and that Fgf2 and its receptor, Fgfr-1, are downregulated by mid to late stages of neurogenesis. In Fgf2 knockout mice, the volume and cell number of the dorsal PVE (the cerebral cortical anlage) are substantially smaller, whereas the volume of the basal PVE is unchanged. The dorsal PVE of Fgf2 knockout mice has a 50% decrease in founder cells and a reduced expansion of the progenitor pool over the first portion of neurogenesis. Despite this reduction, the degree of apoptosis within the PVE is not changed in the Fgf2 knockouts. Cortical neuron number was decreased by 45% in Fgf2 knockout mice by the end of neurogenesis, whereas the number of neurons in the basal ganglia was unaffected. Microscopically, the frontal cerebral cortex of neonatal Fgf2 null mutant mice lacked large neurons in deep cortical layers. We suggest that Fgf2 is required for the generation of a specific class of cortical neurons arising from the dorsal PVE.

Animals↗
PubMed2000

Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders.

BACKGROUND: Previous studies have provided preliminary serological evidence supporting the theory that symptoms of tic disorders or obsessive-compulsive disorder (OCD) may be sequelae of prior streptococcal infection. It is unclear, however, whether previously reported associations with streptococcal infection were obscured by the presence of diagnostic comorbidities. It is also unknown whether streptococcal infection is associated in vivo with anatomical alterations of the brain structures that have been implicated in the pathophysiology of these disorders. METHODS: Antistreptococcal antibody titers were measured in 105 people diagnosed as having CTD, OCD, or attention-deficit/hyperactivity disorder (ADHD) and in 37 community controls without a disorder. Subjects were unselected with regard to their history of streptococcal exposure. Basal ganglia volumes were measured in 113 of these subjects (79 patients and 34 controls). RESULTS: A DSM-IV diagnosis of ADHD was associated significantly with titers of 2 distinct antistreptococcal antibodies, antistreptolysin O and anti-deoxyribonuclease B. These associations remained significant after controlling for the effects of CTD and OCD comorbidity. No significant association was seen between antibody titers and a diagnosis of either CTD or OCD. When basal ganglia volumes were included in these analyses, the relationships between antibody titers and basal ganglia volumes were significantly different in OCD and ADHD subjects compared with other diagnostic groups. Higher antibody titers in these subjects were associated with larger volumes of the putamen and globus pallidus nuclei. CONCLUSIONS: These findings suggest that the prior reports of an association between antistreptococcal antibodies and either CTD or OCD may have been confounded by the presence of ADHD. They also support the hypothesis that in susceptible persons who have ADHD or OCD, chronic or recurrent streptococcal infections are associated with structural alterations in basal ganglia nuclei.

Adult↗
PubMed2000

Patterns of response to acute naloxone infusion in Tourette's syndrome.

The purpose of this study was to replicate findings from an earlier pilot study in which we found a dose-related effect of the opioid antagonist naloxone on tic behavior in patients with Tourette's syndrome (TS). Fifteen subjects with TS were challenged with randomized doses (30 and 300 microg/kg) of naloxone at 3-day intervals. Videotaped recordings of tic behavior were counted in a "blind" fashion. We found that naloxone had opposite effects on tics at different dosages. The low dose caused a significant decrease in tics, whereas the high dose caused a significant increase in tics. Therefore, activity at opioid receptors appears to influence the expression of TS, and the difference in response to naloxone in TS subjects may be based on a dose-response effect.

Adult↗
PubMed2000

Risperidone-associated weight gain in children and adolescents: a retrospective chart review.

OBJECTIVE: Risperidone use has been associated with substantial weight gain in children and adolescents. Reports available to date have consisted of small case series evaluated without standardized indices of developmentally normative weight increase. The purpose of this study was to evaluate age- and gender-adjusted weight changes linked to risperidone use in a juvenile psychiatric inpatient population. METHOD: Thirty-seven child and adolescent inpatients treated with risperidone for 6 consecutive months were compared to a group of 33 psychiatric inpatients with no atypical neuroleptic exposure. Weight, height, and body mass index (BMI) were recorded on at least a monthly basis, and Tanner staging was completed on admission. Percent change from baseline weight, changes in standardized z scores of weight for age and gender, and proportion of subjects experiencing a < or = 7% weight increase from baseline were compared among groups. RESULTS: Subjects in both groups were comparable at baseline except for gender distribution (more males were in the risperidone group, p < 0.05). Risperidone-treated children and adolescents experienced significant weight gain between baseline and endpoint (paired t test, p < 0.001) that was first evident within 2 months of starting treatment, progressed steadily at an average rate of 1.2 kg/month, and did not reach a clear plateau during 6 months of observation. Significant increases in standardized weight were noted at 3 and 6 months for risperidone-treated subjects. Risperidone use conferred a substantial risk of gaining over 7% from baseline weight (odds ratio = 3.5, 95% confidence interval = 1.8-6.6, p < 0.001). CONCLUSIONS: Six-month exposure to risperidone was associated with clinically significant weight gain in 78% of treated children and adolescents (as opposed to 24% of those in the comparison group, p < 0.001). Risperidone dosage, concomitant medication use, and other demographic characteristics such as age, pubertal status, gender, and baseline weight and BMI were not associated with an increased risk of morbid weight gain. Standardized z scores offer advantages for the assessment of weight change among developing children and adolescents.

Adolescent↗
PubMed2000

The genetics of childhood psychiatric disorders: a decade of progress.

OBJECTIVE: To review the literature over the past decade on the genetics of childhood neuropsychiatric disorders. METHOD: A computerized search was performed for articles published in the past decade, and selected papers were highlighted. RESULTS: The past decade of research has illuminated the complex genetics of early-onset mental disorders. Advances in statistical methodologies and laboratory-based gene-hunting techniques are laying the foundation for a deeper understanding of both the biological and environmental factors that contribute to mental illness. Researchers are on the verge of identifying and characterizing genetic vulnerabilities involved in common childhood psychiatric syndromes. CONCLUSIONS: Although the study of the genetics of childhood psychiatric disorders has advanced significantly over the past decade, considerable work remains. The identification of genes conferring vulnerability to psychiatric illnesses will have the potential to transform the field by providing insight into both biological and environmental determinants that contribute to serious developmental and psychiatric disorders in children and adolescents. These advances promise new understanding and new avenues for prevention and treatment. They will also present physicians and families with significant clinical and ethical challenges.

Child↗
PubMed2000

The psychiatric symptoms of rheumatic fever.

OBJECTIVE: This study examined the frequency and age at onset of psychiatric disorders among children with rheumatic fever, Sydenham's chorea, or both and a comparison group. METHOD: Twenty children with rheumatic fever, 22 with Sydenham's chorea, and 20 comparison children were assessed by means of a semistructured interview and rating scales for tic disorders and obsessive-compulsive disorder. RESULTS: Obsessive-compulsive symptoms were more frequent in both the Sydenham's chorea and rheumatic fever groups than in the comparison group. The Sydenham's chorea group had a higher frequency of major depressive disorder, tic disorders, and attention deficit hyperactivity disorder (ADHD) than both the comparison and rheumatic fever groups. ADHD symptoms were associated with a higher risk of developing Sydenham's chorea. CONCLUSIONS: Both the rheumatic fever and Sydenham's chorea groups were associated with a higher risk of developing neuropsychiatric disorders than the comparison group. ADHD appears to be a risk factor for Sydenham's chorea in children with rheumatic fever.

Age Factors↗
PubMed2000

Sensory phenomena in obsessive-compulsive disorder and Tourette's disorder.

BACKGROUND: Recent studies have suggested that obsessive-compulsive disorder (OCD) is a heterogeneous disorder with some forms related to tics and Tourette's disorder. The present study was undertaken to investigate the sensory phenomena in patients with OCD and/or Tourette's disorder to determine if these phenotypic features represent valid clinical indices for differentiating tic-related OCD from non-tic-related OCD. METHOD: We evaluated 20 adult outpatients with OCD, 20 with OCD plus Tourette's disorder, and 21 with Tourette's disorder, using a semistructured interview designed to assess several definitions of sensory phenomena reported in the literature. DSM-III-R criteria were used for the OCD and Tourette's disorder diagnoses. RESULTS: Sensory phenomena including bodily sensations, mental urges, and a sense of inner tension were significantly more frequent in the 2 Tourette's disorder groups when compared with the OCD alone group. Feelings of incompleteness and a need for things to be "just right" were reported more frequently in the OCD plus Tourette's disorder group compared with the other 2 groups. CONCLUSION: Sensory phenomena may be an important phenotypic measure for grouping patients along the OCD-Tourette's disorder spectrum. Sensory phenomena include bodily and mental sensations. Bodily sensations include focal or generalized body sensations (usually tactile, muscular-skeletal/visceral, or both) occurring either before or during the patient's performance of the repetitive behaviors. These sensations are more frequently found in patients with OCD plus Tourette's disorder than in patients with OCD alone. Mental sensations include urge only, energy release (mental energy that builds up and needs to be discharged), incompleteness, and just-right perceptions. They are all more frequently found in patients with OCD plus Tourette's disorder than in patients with OCD alone.

Adult↗
PubMed2000

Pharmacologic treatment of tic disorders.

The approach to treating children and adolescents with tic disorders has evolved in recent years such that complete elimination of tics is no longer the primary goal of treatment. Indeed, given the high frequency of psychiatric comorbidity in TS, treatment planning begins with identification of target symptoms. Although traditional neuroleptics still represent standard treatment for tics, many families and clinicians are reluctant to use these agents because of concern about the potential for short- and long-term side effects. Thus, there is great interest in the newer atypical neuroleptics. Interest in the atypical neuroleptics is understandable, but much more study is needed before these agents can become first-line treatments for tics. A small group of non-neuroleptic medications have been used in the treatment of tics. Of these, clonidine, guanfacine, tetrabenazine, pergolide, and botulinum toxin injections have shown some promise for suppressing tics. To date, however, only clonidine has been evaluated in randomized, controlled trials, and the results are not consistent across studies. Although comorbid ADHD is common in children with TS, treatment with stimulant medications was not recommended in children with tics. Recent data suggest that stimulants may be used in some children with TS without adverse effects. Until more is known about which children with ADHD and tic disorders can be safely treated with stimulants, however, the use of stimulants in this population should be undertaken with caution. A handful of nonstimulant medications have been used in the treatment of ADHD with some success, but more study is needed for most of these agents. Evaluation of the stimulants and nonstimulants for the treatment of ADHD in children and adolescents with tic disorders is an area worthy of large controlled trials.

Adolescent↗
PubMed2000

Social and emotional adjustment in children affected with Gilles de la Tourette's syndrome: associations with ADHD and family functioning. Attention Deficit Hyperactivity Disorder.

This study examined social-emotional functioning in children with Gilles de la Tourette's syndrome (TS) alone and children with TS and Attention Deficit Hyperactivity Disorder (ADHD). In addition, the contribution of family functioning to social competence was examined. Children with a clinical diagnosis of TS were recruited from the Yale Child Study Center TS specialty clinic. Unaffected control children were recruited through newspaper advertisements and announcements within the university and at area schools. The final sample consisted of 72 children (45 boys and 27 girls) between the ages of 8 and 14. Sixteen children met DMS-III-R criteria for TS, 33 children met criteria for TS and ADHD, and 23 children had no psychiatric diagnoses. Children with TS and ADHD evidenced more externalizing and internalizing behavior problems and poorer social adaptation than children with TS only or unaffected controls. Children with TS only were not significantly different from unaffected controls on most measures of externalizing behaviors and social adaptation but did exhibit more internalizing symptoms. Tic symptom severity was not associated with social, behavioral, or emotional functioning among children with TS, even after stratifying by medication status. However, ADHD diagnosis, obsessional symptom severity, and family functioning were significantly associated with social and emotional adjustment among TS children. Moreover, family functioning was associated with social and emotional adjustment even after controlling for TS and ADHD diagnostic status. These findings demonstrate that much of the social and behavioral dysfunction in children with TS is ADHD-specific and children with TS alone have a very different social-emotional profile than do those with TS plus ADHD. Finally, social-emotional adjustment in children with TS is best understood within the family context.

Adaptation, Psychological↗
PubMed1999

Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores.

Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder characterized by recurring obsessions or compulsions that cause significant distress to the patient or significantly interfere with the patient's normal home, work, or social activities [Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC: American Psychiatric Association, 1994]. Twin and family studies have suggested that OCD has a significant genetic component. We performed complex segregation analyses using POINTER with families ascertained through an OCD-affected proband. In an attempt to resolve the phenotypic heterogeneity observed among individuals with OCD these segregation analyses used four factor-analytic symptom dimensions to subset the family sample based upon probands' symptom factor scores. Analysis of the entire sample allowed rejection of only the no transmission model; that model was also rejected in all subsequent analyses. Limiting the analyses to families with at least one OCD-affected member in addition to the proband (the demonstrably familial form of OCD) allowed rejection of all models except the mixed model. Analyses limited to families of high-factor-3 (symmetry and ordering symptoms) probands led to rejection of the polygenic model, indicating the involvement of a major locus. Additionally, the relative risk of OCD or subclinical OCD was 1.7 for relatives of probands with a factor 3 score greater than zero compared with relatives of probands with a low factor score. The symptoms attributed to high factor 3 scores (symmetry and ordering) may constitute a genetically significant symptomatic subtype of OCD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:669-675, 1999.

Aging↗
PubMed1999

The Tourette syndrome diagnostic confidence index: development and clinical associations.

BACKGROUND: The clinical characteristics of Tourette syndrome (TS) present challenges for the systematic determination of whether individuals are affected and severity. Vocal and motor tics wax and wane, decrease over time, and may be voluntarily suppressible, and therefore may be absent at interview. Current instruments measure symptoms at interview or rate symptom severity only. METHOD: To minimize error in case ascertainment and produce an instrument measuring lifetime likelihood of having had TS, clinical members of the American Tourette Syndrome Association International Genetic Collaboration developed the Diagnostic Confidence Index (DCI). The expert group worked collaboratively with progressive revision in consensus workshops using existing diagnostic criteria as guidelines. The DCI produces a score from 0 to 100 that is a measure of the likelihood of having or ever having had TS. RESULTS: The DCI was administered to 280 consecutive patients with TS attending a TS clinic; 264 (94%) completed it, indicating high feasibility and acceptability. Its correlation with other instruments and associations with psychopathology provide support for its being a lifetime measure of TS. CONCLUSIONS: The DCI is a useful, practicable instrument in the clinic or research practice allowing an assessment of lifetime likelihood of TS. Further work is needed to test the DCI's psychometric properties, such as its validity and reliability in populations of interest.

Adolescent↗
PubMed1999

Identification, chromosomal assignment, and expression analysis of the human homeodomain-containing gene Orthopedia (OTP).

Homeodomain (HD) genes are helix-turn-helix transcription factors that play key roles in the specification of cell fates. In the central nervous system (CNS), HD genes not only position cells along an axis, but also specify cell migration patterns and may influence axonal connectivity. In an effort to identify novel HD genes involved in the development of the human CNS, we have cloned, characterized, and mapped the human homologue of the murine HD gene Orthopedia (Otp), whose product is found in multiple cell groups within the mouse hypothalamus, amygdala, and brain stem. Human cDNA and genomic libraries were screened with probes derived from mouse Otp sequences to find the human homologue, OTP. The deduced amino acid sequence of the open reading frame of the human cDNA is 99% homologous to mouse Otp and demonstrates a high degree of conservation when compared to sea urchin and Drosophila. OTP was mapped to human chromosome 5q13.3 using radiation hybrid panel mapping and fluorescence in situ hybridization. Flanking markers were identified from YAC clones containing OTP. A single putative OTP gene product was found in 17-week human fetal brain tissue by Western blot analysis using a novel polyclonal antibody raised against a conserved 13-amino-acid sequence at the C-terminus of the OTP protein. Expression in the developing human hypothalamus was confirmed by immunohistochemistry.

Amino Acid Sequence↗
PubMed1999

Oxytocin, vasopressin, and autism: is there a connection?

Autism is a poorly understood developmental disorder characterized by social impairment, communication deficits, and compulsive behavior. The authors review evidence from animal studies demonstrating that the nonapeptides, oxytocin and vasopressin, have unique effects on the normal expression of species-typical social behavior, communication, and rituals. Based on this evidence, they hypothesize that an abnormality in oxytocin or vasopressin neurotransmission may account for several features of autism. As autism appears to be a genetic disorder, mutations in the various peptide, peptide receptor, or lineage-specific developmental genes could lead to altered oxytocin or vasopressin neurotransmission. Many of these genes have been cloned and sequenced, and several polymorphisms have been identified. Recent gene targeting studies that alter expression of either the peptides or their receptors in the rodent brain partially support the autism hypothesis. While previous experience suggests caution in hypothesizing a cause or suggesting a treatment for autism, the available preclinical evidence with oxytocin and vasopressin recommends the need for clinical studies using gene scanning, pharmacological and neurobiological approaches.

Autistic Disorder↗
PubMed1999

The rituals, fears and phobias of young children: insights from development, psychopathology and neurobiology.

This study examined the relationship between ritualistic, compulsive-like behaviors and normative fears and phobias in 61 children ranging from 1 to 7 years of age. Parents reported on their children's ritualistic habits, and perfectionistic behaviors that reflect what we have previously called "compulsive-like" behaviors. Parents also reported on their children's fears and phobias. Results indicated that various aspects of children's ritualistic and compulsive-like behaviors are correlated with children's fears and phobias. Developmental differences existed such that younger children's (< 4 years) repetitive, compulsive-like behaviors were related to "prepotent" fears such as stranger and separation anxieties, whereas the compulsive-like behaviors of older children (> 4 years) were correlated with more specific, "contextual" fears such as fears of contamination, death, and fears often associated with concerns of the inner city such as burglars, assault, etc. These findings are discussed in terms of the phenomenologic and possible neurobiological continuities between normative and pathologic rituals, fears and phobias.

Ceremonial Behavior↗
PubMed1999

Psychosocial and clinical correlates of ADHD in a community sample of school-age children.

OBJECTIVE: To identify the psychosocial and clinical correlates of attention-deficit hyperactivity disorder (ADHD) in a community sample of children and to examine the validity of a subclinical form of ADHD. METHOD: The sample of 449 children (mean age 9.2 years, SD 1.78; 53.6% boys) participated in the second stage of a community survey. Of these, 359 (80%) screened positive at stage 1. On the basis of a structured diagnostic interview with a parent, children were classified into 1 of 3 mutually exclusive groups: ADHD (n = 89), subthreshold ADHD (n = 100), and non-ADHD (n = 260). RESULTS: As measured by the Children's Global Assessment Scale, the ADHD group was more impaired than the subthreshold group, which was more impaired than the non-ADHD group (p < .05 for each test). Children in the ADHD group were more likely to be male, to have mothers with a history of psychiatric treatment, to have fathers with a history of excessive alcohol use, and to live in low-income families with higher levels of family dysfunction (p < .05 for all variables). A model containing male gender, family dysfunction, and low income was most predictive of ADHD status (p < .01). ADHD was also associated with psychiatric comorbidity, especially disruptive behavior disorders. CONCLUSIONS: These results support a dimensional approach to ADHD. More severe forms of ADHD are associated with psychosocial adversity and psychiatric comorbidity.

Analysis of Variance↗