A spontaneous albino mutant of Ceratocystis resinifera results from a point mutation in the polyketide synthase gene, PKS1.

We characterized a spontaneous albino mutant of Ceratocystis resinifera. Compared with the wild-type progenitor strain, the albino mutant had a reduced linear growth on culture medium, but its growth on lodgepole pine sapwood was unaffected. The albino mutant did not produce any coloured pigment on agar media or wood. However, upon exposure to exogenous scytalone, an intermediate metabolite of the melanin pathway, the production of a brownish melanin was restored. This suggests that the albino phenotype resulted from a mutation affecting the melanin synthesis pathway, upstream of the scytalone synthesis step. Melanin production was restored in the mutant by transforming it with a wild-type copy of the Ceratocystis resinifera polyketide synthase gene, PKS1. The complemented transformants produced melanin, indicating that the PKS1 gene was defective in the albino mutant. Sequence analysis revealed that the PKS1 allele found in the albino contained a single point mutation that resulted in an amino acid change from serine to proline at the 3' end of the beta-ketoacyl synthase motif.

Establishment of a gene transfer system for Pseudozyma flocculosa, an antagonistic fungus of powdery mildew fungi.

A reliable DNA-mediated transformation system has been developed for Pseudozyma flocculosa, a fungus that is antagonistic to powdery-mildew fungi. Plasmids harboring various selectable markers under the control of different promoters were tested. Molecular analyses demonstrated that successful transformation could be achieved using a plasmid that confers resistance to hygromycin B under the control of the Ustilago maydis hsp70 promoter and terminator sequences. On average, 1-40 (mean = 20) transformants were obtained per 10 microg of linearized DNA per 10(8) protoplasts. Southern analysis of the transformants revealed that, in each case, the vector had integrated in multiple tandem copies into the genome of P. flocculosa, and that integration events were random. Pulsed-field gel electrophoresis was employed to separate the genome of P. flocculosa into at least 11 chromosomes with sizes ranging from 0.55 Mb to 2.9 Mb. Hybridization with the plasmid indicated that integration of vector DNA had occurred in one to several chromosomes depending on the transformant examined.

Pervasive developmental disorders: a 10-year review.

OBJECTIVE: To summarize recent advances about the nature, diagnosis, and treatment of pervasive developmental disorders. METHOD: Review of Medline databases, books, and book chapters published between July 1989 and November 1999. RESULTS: Clinical and genetic studies support expansion of the concept of autism to include a broader spectrum of social communication handicaps. The prevalence of autism is approximately 1 per 2,000; the prevalence of autism and Asperger's disorder together is 1 per 1,000. The Checklist for Autism in Toddlers is a useful screening instrument for 18-month-old children; the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule are instruments of choice for research. Although twin and family studies clearly support genetic factors as important in autism, linkage analysis studies indicate that many genes may be involved. There is no one treatment of choice. Social-pragmatic approaches, augmented by individualized strategies and social coaching, may be best for teaching social communication skills. Pharmacological interventions have a limited role in improving social communication, but selective serotonin reuptake inhibitors and atypical neuroleptic medications may help ameliorate aggression, hyperactivity, and other secondary problems. CONCLUSIONS: Private and government agencies must continue to support basic and applied research.

Summary of the 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.

This summary provides an overview of the assessment and treatment recommendations contained in the Practice Parameters for the Assessment and Treatment of Children, Adolescents, and Adults With Autism and Other Pervasive Developmental Disorders. The parameters were written to aid clinicians in the assessment and treatment of children and adolescents with autism and other pervasive developmental disorders. 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.

Domains of social communication handicap in autism spectrum disorder.

OBJECTIVE: To investigate whether specific "social communication" handicaps could be identified in autism spectrum disorder using the Autism Diagnostic Observation Schedule and to compare the results with those found in a previous factor-analysis study using the Autism Diagnostic Interview-Revised. METHOD: All subjects were evaluated with both instruments. J.R. and P.E.T. independently diagnosed autism, Asperger's disorder, or pervasive developmental disorder--not otherwise specified in 51 children. Items from the Autism Diagnostic Observation Schedule that represented social communication behaviors were factor-analyzed. RESULTS: Three factors were identified: joint attention, affective reciprocity, and theory of mind. These are the same social communication domains that were identified in the previous study. CONCLUSIONS: These 3 social communication domains have been discussed in the literature regarding normal development and in previous research on autism spectrum disorders. If these domains are replicated in larger sample sizes, they could be used to monitor the results of pharmacological and psychotherapeutic interventions in autism spectrum disorders.

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).

Autism in tuberous sclerosis complex.

The frequency and clinical presentation of autism in 28 probands with tuberous sclerosis complex (TSC) are reported and risk factors that may influence the development of autism in TSC are examined. Eight probands meet ICD-10 and DSM-IV criteria for autism, an additional 4 meet criteria for pervasive developmental disorder (PDD). Twelve TSC probands with autism/PDD are compared to 16 TSC probands without these conditions for factors which may underlie the association of autism and TSC. A specific seizure type, infantile spasms, as well as mental retardation, are increased in the TSC, autistic/PDD group. Furthermore, rates of social phobia and substance abuse are elevated among first-degree relatives of TSC probands with autism compared to first-degree relatives of TSC probands without autism. Implications of these findings in understanding the association of autism and TSC are discussed.

A dimensional classification of autism spectrum disorder by social communication domains.

OBJECTIVE: To investigate whether "social communication" could be used to assess severity of symptoms in autism spectrum disorder. Social communication refers to the communication of cognitive and emotional information through facial expression, gesture, and prosody and through implicit understanding of pragmatics and of theory of mind. METHOD: Subjects were evaluated by raters using the Autism Diagnostic interview-Revised and either the Autism Diagnostic Observation Schedule or the Pre-Linguistic Autism Diagnostic Observation Schedule. Two investigators independently diagnosed autism, Asperger's disorder, or pervasive developmental disorder-not otherwise specified in 63 subjects. Items from the Autism Diagnostic Interview-Revised that were judged to represent social communication behaviors were factor-analyzed. RESULTS: Three factors were identified: affective reciprocity, joint attention, and theory of mind. Comparing this new classification approach to DSM-IV led to suggestions for possible changes in the latter: (1) Vocabulary and grammar deficiencies in autistic persons should be coded under developmental language disorder, (2) The diagnosis of Asperger's disorder may not be needed. (3) Requiring that all persons with autism spectrum disorder have a symptom from the "restrictive, repetitive, and stereotypic" list may need to be reconsidered. CONCLUSIONS: The DSM-IV category of pervasive developmental disorder may be ideal for diagnosing "classic" autism, but it may be inadequate for diagnosing less severe forms of the disorder.

Case study: the use of melatonin in a boy with refractory bipolar disorder.

The authors describe the clinical course of a 10-year-old boy with bipolar disorder diagnosed at age 5 years. Lithium, carbamazepine, and valproic acid were ineffective or caused intolerable side effects. A trial of melatonin led to rapid relief of insomnia and aborted a manic episode. He has continued to take melatonin and adjunctive alprazolam for 15 months without recurrence of insomnia or mania. Affective disorders involving circadian dysregulation may respond to interventions that restore a normal sleep-wake cycle. Literature supporting this hypothesis is cited.

Autism, affective disorders, and social phobia.

The purpose of this study is to test the hypothesis that major affective and/or anxiety disorders are increased among relatives of autistic probands compared with controls. Among 36 families with an autistic child, 23 (64%) have a first degree relative diagnosed with major depressive disorder and 14 (39%) have a first degree relative diagnosed with social phobia. These rates are significantly greater than the 19% and 5%, respectively, found among 21 families with a child having a genetic condition, tuberous sclerosis complex, or a seizure disorder but no autism. The frequency of major depression among the 96 first degree relatives of autistic probands is 37.5% compared with 11.1% found among 45 relatives of control probands. The frequency of social phobia, 20.2%, is approximately 10 times more common than that found among the relatives of the control probands (2.4%). Elevated rates of both major depression and social phobia are found among parents and siblings in the families with an autistic child. Furthermore, 64% of parents affected with a major depression had the onset of the first depressive episode prior to the birth of the autistic child and all parents with social phobia had the onset of condition prior to the birth of the autistic child. Family patterns differ depending on the intellectual level of the autistic child; specifically, social phobia is significantly greater among the first degree relatives of non-retarded autistic probands than among relatives of individuals with autism and comorbid mental retardation.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliability of the Part II board certification examination in psychiatry: examination stability.

OBJECTIVE: The aim of this study was to examine the reliability (examination stability) of the American Board of Psychiatry and Neurology (ABPN) Part II (oral) examination in psychiatry. METHOD: The authors analyzed the consistency (agreement between grades given by two independent examiners) for a 1-year examination cycle using a weighted kappa statistic and compared different parts of the examination (live patient and videotape), different examination sites, different days, and different times of the day. RESULTS: There was no significant difference in agreement between examiners by different parts of the examination, examination site, day of the week, or time of day. CONCLUSIONS: The stability of the Part II ABPN examination in psychiatry is not influenced significantly by the format or site of administration. Candidate performance is the predominant factor in the determination of passing or failing grades.

An intervention to improve the reliability of manuscript reviews for the Journal of the American Academy of Child and Adolescent Psychiatry.

OBJECTIVE: The effects of methods used to improve the interrater reliability of reviewers' ratings of manuscripts submitted to the Journal of the American Academy of Child and Adolescent Psychiatry were studied. METHOD: Reviewers' ratings of consecutive manuscripts submitted over approximately 1 year were first analyzed; 296 pairs of ratings were studied. Intraclass correlations and confidence intervals for the correlations were computed for the two main ratings by which reviewers quantified the quality of the article: a 1-10 overall quality rating and a recommendation for acceptance or rejection with four possibilities along that continuum. Modifications were then introduced, including a multi-item rating scale and two training manuals to accompany it. Over the next year, 272 more articles were rated, and reliabilities were computed for the new scale and for the scales previously used. RESULTS: The intraclass correlation of the most reliable rating before the intervention was 0.27; the reliability of the new rating procedure was 0.43. The difference between these two was significant. The reliability for the new rating scale was in the fair to good range, and it became even better when the ratings of the two reviewers were averaged and the reliability stepped up by the Spearman-Brown formula. The new rating scale had excellent internal consistency and correlated highly with other quality ratings. CONCLUSIONS: The data confirm that the reliability of ratings of scientific articles may be improved by increasing the number of rating scale points, eliciting ratings of separate, concrete items rather than a global judgment, using training manuals, and averaging the scores of multiple reviewers.

Autistic children and the object permanence task.

Many mentally retarded autistic children can understand the concept of object permanence, but, in comparison to developmental-age matched normal children, the behavioral strategies they employ in carrying out the Casati-Lezine Object Permanence Test are deficient and lead to failure. These deficiencies appear unrelated to interference of stereotypic or other bizarre behavior in task performance. Similar problem-solving deficiencies can be found in mentally retarded children who are not autistic, suggesting that the deficiencies themselves are less related to the social-communication deficits of autistic children, but more to the general problem-solving difficulties found in children with a lower developmental quotient. Nevertheless, the qualitative analysis of results shows a tendency in autistic children, despite their better developmental level, to use less coordinated and regular sequences to solve the task than normal or mentally retarded children.

Autism and tuberous sclerosis.

Autism is a behavior disorder with genetic influences indicated from twin and family studies and from the co-occurrence of autism with known genetic disorders. Tuberous sclerosis complex (TSC) is a known genetic disorder with behavioral manifestations including autism. A literature review of these two disorders substantiates a significant association of autism and TSC with 17-58% of TSC subjects manifesting autism and 0.4-3% of autistic subjects having TSC. In initial data collected on 13 TSC probands and 14 autistic probands in our family study of autism and TSC, we identified 7 TSC subjects with autism. The seven TSC autistic probands are similar to non-TSC autistic probands on the Social and Communication domains of the Autism Diagnostic Inventory (ADI) (Le Couteur et al., 1989), but show fewer Repetitive Rituals. There are more male TSC probands with autism than female, despite an equal sex ratio among TSC probands. The TSC probands with autism have significantly more seizures and mental retardation than those without autism; however, the extent and etiology of associations require further study. Our preliminary findings suggest that a fruitful approach for delineating genetic influences in autism may come from further investigation of possible mechanisms underlying the association of autism and TSC.

Midlatency auditory evoked responses: P1 abnormalities in adult autistic subjects.

MLR recordings from a group of 11 high-functioning adult autistic subjects were compared with those from a control group of 11 normal subjects. Components selected for analysis were "Pa", the maximum positivity in the 25-40 msec latency range following stimulus onset, "P1", the maximum positivity within the 50-65 msec latency range, and "Nb," the maximum negative deflection in the 40-50 msec latency range. Statistical analyses of amplitude and latency data were conducted using repeated measures analysis of variance and t test group comparisons. The Pa component showed no significant difference between autistic and control groups. However, 2 types of abnormality were noted in the P1 component: (1) the P1 component was significantly smaller in the autistic subjects at slow rates of stimulation, and (2) the autistic P1 did not change as rates of click stimulation increased from 0.5 to 10/sec, in contrast to the normally produced P1 decrement. Data from the P1 model in the cat, and complementary data from the human, closely link the generator substrate of the P1 potential to cholinergic components of the ascending reticular activating system (RAS) and their thalamic target cells. This is the first report of abnormal P1 responses in autism and strongly suggests that the RAS and/or its post-synaptic thalamic targets may be dysfunctional in this syndrome.

Regional cerebral glucose metabolism and attention in adults with a history of childhood autism.

Sixteen high-functioning adults with a history of childhood autism and 26 normal control subjects underwent [18F]fluoro-2-deoxyglucose positron-emission tomography to assess regional cerebral glucose metabolic rate (GMR). Autistic patients had a left > right anterior rectal gyrus asymmetry, as opposed to the normal right > left asymmetry in that region. Patients also showed low GMR in the left posterior putamen and high GMR in the right posterior calcarine cortex. Brain regions with GMR > 3 SD from the normal mean were more prevalent in patients than in control subjects. This variable pattern of abnormal activity is consistent with heterogeneous neurophysiological etiology; group differences in striatum and cortex may represent a final common pathway.

Reliability of the Part II Board Certification Examination in Psychiatry: interexaminer consistency.

OBJECTIVE: The aim of the study was to examine the reliability (interexaminer consistency) of the American Board of Psychiatry and Neurology (ABPN) Part II (oral) examination in psychiatry. METHOD: Grades were assigned independently by two examiners who observed the same examination in a 1-year cycle (1,422 candidates, two examinations each). The consistency between these pairs of grades (pass, condition, fail) was analyzed using a weighted kappa statistic. RESULTS: There was perfect agreement between examiners in 67% of examinations, minor disagreement in 26%, and major disagreement in 7% (weighted kappa = 0.54-0.56). CONCLUSIONS: The Part II ABPN examination demonstrates fair to good reliability as measured by interexaminer consistency. Development of more explicit grading criteria should further improve examiner agreement in future examinations.

P3 responses to prosodic stimuli in adult autistic subjects.

Autistic persons are known to have serious abnormalities in speech prosody. The present study attempted to ascertain whether autistic persons could discriminate and/or recognize prosodic contrasts in auditory stimuli. A group of 11 adult autistic subjects with normal IQ and an age-matched group of normal subjects were studied electrophysiologically and behaviorally during presentations of prosodic and phonemic stimuli. The cognitive P3 potential was recorded in response to rare (20%)/frequent (80%) presentations of phonemic stimuli, 'ba/pa,' linguistic-prosodic stimuli, 'Bob.' (statement)/'Bob?' (question), and emotional-prosodic stimuli, 'Bob' (happy)/'Bob' (angry). Behaviorally, auditory discrimination was tested by requiring a button-press response to each presentation of the rare target stimulus and cognitive association was tested by requiring a match between the verbalized stimulus and an appropriate picture/word. Contrary to our hypothesis, the autistic subjects generally showed normal P3 responses to all stimuli and performed at a normal level in all behavioral tests. However, a significant autistic P3 response to the phoneme 'pa' was not demonstrated. This surprising result was reexamined and shown to reflect an unusually large autistic response to 'pa' as the frequent stimulus in the first recording block, this initial hyper-reactivity prevented a 'frequent/rare' differential when 'pa' was presented as the rare stimulus in a later recording block. In the P3 latency window, both the autistic and control groups showed the largest amplitude responses to emotional-prosodic stimuli; neither the N1 nor P2 showed these stimulus effects. Thus, 'emotional sounds' appear to be particularly effective in activating the neural substrate of the P3 generator system. Overall, these data indicate remarkably normal P3 and behavioral processing of prosodic stimuli by the high-functioning autistic subjects of this study.