Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function.

DNA methylation (DNAm) plays a determining role in neural cell fate and provides a molecular link between early-life stress and neuropsychiatric disease. Preterm birth is a profound environmental stressor that is closely associated with alterations in connectivity of neural systems and long-term neuropsychiatric impairment. The aims of this study were to examine the relationship between preterm birth and DNAm, and to investigate factors that contribute to variance in DNAm. DNA was collected from preterm infants (birth<33 weeks gestation) and healthy controls (birth>37 weeks), and a genome-wide analysis of DNAm was performed; diffusion magnetic resonance imaging (dMRI) data were acquired from the preterm group. The major fasciculi were segmented, and fractional anisotropy, mean diffusivity and tract shape were calculated. Principal components (PC) analysis was used to investigate the contribution of MRI features and clinical variables to variance in DNAm. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants compared with controls; 10 of these have neural functions. Differences detected in the array were validated with pyrosequencing. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 PCs; corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Preterm birth is associated with alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for understanding the genetic/epigenetic basis of preterm brain injury.

Evaluation of a patterning treatment for retarded children.

Three groups, each with 15 seriously retarded institutionalized children, were employed to evaluate a modification of the sensorimotor patterning treatment developed at the Institutes for the Achievement of Human Potential (IAHP). The treatment group received a program modeled after the IAHP methods for approximately two hours per day, five days per week, for one year. For the same length of time, a matched motivational control group participated in activities with foster grandparents designed to create positive, success-oriented interactions to improve self-esteem and feelings of efficacy. A no treatment group continued to receive the standard care of the institution, which was enlightened and resident-oriented. A wide variety of behavioral measures were employed, including the IAHP Developmental Profile, IQ, motor and language development scales, and measures of affective, social, and maladaptive behaviors. On the majority of the measures there were no differences in posttest performance among any of the three groups. In no case did the pattern of change of the treatment group differ from that of its crucial comparison, the motivation group. However, all three groups showed some improvement in performance between the beginning and end of the study. It was concluded that the patterning treatment investigated in this study cannot be recommended for seriously retarded children.

Outcome of children in the indomethacin intraventricular hemorrhage prevention trial.

BACKGROUND: For preterm infants, intraventricular hemorrhage (IVH) may be associated with adverse neurodevelopmental outcome. We have demonstrated that early low-dose indomethacin treatment is associated with a decrease in both the incidence and severity of IVH in very low birth weight preterm infants. In addition, we hypothesized that the early administration of low-dose indomethacin would not be associated with an increase in the incidence of neurodevelopmental handicap at 4.5 years of age in our study children. METHODS: To test this hypothesis, we provided neurodevelopmental follow-up for the 384 very low birth weight survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial. Three hundred thirty-seven children (88%) were evaluated at 54 months' corrected age, and underwent neurodevelopmental examinations, including the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Peabody Picture Vocabulary Test-Revised (PPVT-R), and standard neurologic examinations. RESULTS: Of the 337 study children, 170 had been randomized to early low-dose indomethacin therapy and 167 children had received placebo. Twelve (7%) of the 165 indomethacin children and 11 (7%) of the 158 placebo children who underwent neurologic examinations were found to have cerebral palsy. For the 233 English-monolingual children for whom cognitive outcome data follow, the mean gestational age was significantly younger for the children who received indomethacin than for those who received placebo. In addition, although there were no differences in the WPPSI-R or the PPVT-R scores between the 2 groups, analysis of the WPPSI-R full-scale IQ by function range demonstrated significantly less mental retardation among those children randomized to early low-dose indomethacin (for the indomethacin study children, 9% had an IQ <70, 12% had an IQ of 70-80, and 79% had an IQ >80, compared with the placebo group, for whom 17% had an IQ <70, 18% had an IQ of 70-80, and 65% had an IQ >80). Indomethacin children also experienced significantly less difficulty with vocabulary skills as assessed by the PPVT-R when compared with placebo children. CONCLUSIONS: These data suggest that, for preterm neonates, the early administration of low-dose indomethacin therapy is not associated with adverse neurodevelopmental function at 54 months' corrected age.

The effect of the trichothecene mycotoxin diacetoxyscirpenol on nitrosamine-induced esophageal cancer in the rat.

The fact that the only chemicals known to be potent carcinogens for the esophagus in animals are certain nitrosamines suggests that these environmental carcinogens could be a cause of human esophageal cancer. Epidemiological investigations support this concept. The level of exposure alone is not considered sufficient to account for the very high incidence of the disease in certain regions, but potentiating factors have been shown to have a dramatic effect on nitrosamine-induced esophageal cancer in animal experiments. A likely enhancing factor is consumption of food contaminated by molds, especially by Fusaria spp, a group known to produce trichothecene mycotoxins. The effect of simultaneous treatment with diacetoxyscirpenol (DS) on methyl-benzyl-nitrosamine (NMBzA)-induced esophageal cancer was studied. Feeding a diet containing DS at 10 ppm for 10 weeks caused thickening of the basal cell layer of the esophageal epithelium, but feeding DS (10 ppm) simultaneously with NMBzA (4, 8, 16 ppm) for 10 weeks, or feeding a lower dose of DS with NMBzA for a longer period, or administration of DS per os at intervals during NMBzA treatment, did not potentiate but possibly reduced esophageal tumors. Toxicity, revealed by reduced growth rate of DS-fed animals, may have inhibited carcinogenesis. In contrast to the rapid potentiating effect of zinc deficiency, DS does not appear to cause an early enhancement of esophageal cancer.

Quantifying social development in autism.

OBJECTIVE: This study was concerned with the development of quantitative measures of social development in autism. METHOD: Multiple regression equations predicting social, communicative, and daily living skills on the Vineland Adaptive Behavior Scales were derived from a large, normative sample and applied to groups of autistic and nonautistic, developmentally disordered children. Predictive models included either mental or chronological age and other relevant variables. RESULTS: Social skills in the autistic group were more than two standard deviations below those predicted by their mental age; an index derived from the ratio of actual to predicted social skills correctly classified 94% of the autistic and 92% of the nonautistic, developmentally disordered cases. CONCLUSIONS: The findings are consistent with the idea that social disturbance is central in the definition of autism. The approach used in this study has potential advantages for providing more precise measures of social development in autism.

Asperger's syndrome.

This Grand Rounds is concerned with the classification of Asperger's syndrome and its continuity/discontinuity with autism. Information on a 15-year-old with the condition is presented as are data on other family members. The proband exhibited a longstanding pattern of marked deficits in social interaction, motor awkwardness, and unusual, circumscribed interest consistent with a diagnosis of Asperger's syndrome. Both the proband and his father exhibited unusual discrepancies between verbal and performance (nonverbal) cognitive abilities favoring the former. Deficits were observed in the social use of language. Father and son had similar abnormalities on magnetic resonance imaging examination. Potential differences between higher-functioning autism and Asperger's syndrome are important areas for future research.

Childhood comorbidity of anxiety/affective disorders and behavior disorders.

Considerable data have been reported concerning comorbidity of various individual psychiatric disorders in children within the diagnostic supradomains of affect/anxiety disorders and behavior disorders as well as between these supradomains. To further examine such comorbidity, 35 psychiatrically hospitalized children were studied in terms of the prevalence of comorbidity, demographic and cognitive characteristics, adaptive functioning and maladaptive behaviors. The prevalence of comorbid behavior + affect/anxiety disorders exceeded 50% of the samples. Children with such comorbidity were similar to children with Behavior only diagnoses in terms of demographic and cognitive characteristics but differed in terms of adaptive functioning and maladaptive behaviors.

Nephrotoxic effect of trimethyltin in rats.

Male Wistar (Porton) rats were dosed by gavage with trimethyltin chloride in arachis oil at doses of 3, 6 and 10 mg/kg. Water consumption and urine production were monitored for 3 days after dosing and at the end of this period the rats were killed and the kidneys were examined histologically. Within 6 h of dosing there was an increase in urine production and in the pH of the urine in all treated groups. Within 24 h of dosing there was an increase in water consumption. Histopathological examination of the kidney at 3 days post-treatment showed nephrotoxic changes ranging from slight vacuolisation of the proximal tubular cells with loss of the brush borders in the 3 mg/kg group to extensive vacuolar degeneration with tubular dilation and evidence of cellular regeneration in the 10 mg/kg group. The results suggest that trimethyltin causes a rapid kidney dysfunction in rats by cytotoxic action on the cells of the proximal tubular epithelium and that this action is dose-related.

A germ-free status does not protect from the lethal effects of acute lung damage caused by O,S,S,-trimethyl phosphorodithioate.

To investigate whether a normal resident microbiological flora of conventional rats influences the lethality of chemical-induced lung damage, the pneumotoxin O,S,S-trimethyl phosphorodithioate (OSSMe, 75 or 100 mg/kg, s.c.) was administered to age-matched conventional and germ-free male F344 rats. Microbiological and serological examinations confirmed the germ-free state of the germ-free rats and showed that no specific lung pathogens were present in the conventional rats. As in conventional rats, clinical symptoms and death of OSSMe-treated germ-free rats resulted from respiratory failure. The germ-free rats were not more resistant, but rather more susceptible to OSSMe than conventional rats. Increases in lung weight and histological examination of lung tissue 3 days after dosing with OSSMe (75 mg/kg, s.c.) showed no differences between germ-free and conventional rats. Despite alterations in their nasopharyngeal flora, death in the conventional rats was probably not caused by bacterial superinfection. The higher susceptibility of germ-free rats to OSSMe can be partly attributed to pharmacokinetic differences, since plasma levels of OSSMe decreased more slowly in germ-free than in conventional rats. It is concluded that germ-free rats are not protected from the lethal consequences of acute chemical-induced lung damage.

Sex differences in pervasive developmental disorders.

Assessed differences in sex ratio, severity of associated mental retardation, and various metrics of severity of autism in autistic, PDD-NOS, and developmentally disordered (non-PDD) cases. Males with autism were more frequent than females, particular at higher IQ levels. The three clinical groups differed, in expected ways, in the various measures of severity of autism with the PDD-NOS cases being intermediate between the strictly diagnosed autistic group and the non-PDD developmental disordered group. Sex differences were primarily confined to IQ; sex differences in other metrics of severity of autism were not prominent. Implications for future research are discussed.

Toward a developmental operational definition of autism.

Traditional approaches to diagnosing autism emphasize delays in communication and socialization. Traditional diagnostic schemes typically list symptoms (e.g., lack of eye contact), but provide little guidance on how to incorporate information about developmental level in making a diagnosis. Because standardized measures of adaptive behavior can provide information about children's communication, socialization, and other behavior relative to their age, they may be useful tools for diagnosing autism. This study investigated the ability of the Vineland Adaptive Behavior Scales to identify children with autism. Vineland scores and measures of intellectual functioning were obtained for children with autism, PDDNOS, and other developmental disorders (DD). Discriminant function analyses indicated that the autism and combined nonautism (PDDNOS and DD) groups could be differentiated on the basis of socialization, daily living skills, and serious maladaptive behaviors. Socialization alone accounted for 48% of the variance in diagnosis. Using regression analyses derived from a large normative sample, adaptive behavior scores were predicted from chronological age (CA) and mental age (MA). Socialization scores in the autism group were substantially below the level predicted from CA or MA. An index derived from the ratio of actual to predicted socialization scores correctly classified 86% of both autism and nonautism cases. Findings suggest that comparison of obtained Vineland socialization scores to those predicted by CA or MA may be useful in clarifying the diagnosis of autism.

An evaluation of the Autism Behavior Checklist.

The Autism Behavior Checklist (ABC), an assessment instrument for autistic individuals, was evaluated in a group of 157 subjects, 94 clinically autistic and 63 nonautistic. The two groups differed significantly in ratings of pathology. Both false positive and false negative diagnostic classifications were made when the results of the checklist were compared with clinical diagnosis. Effects of developmental level and age were observed. The ABC appears to have merit as a screening instrument, though results of the checklist alone cannot be taken as establishing a diagnosis of autism. Important issues of reliability and validity remain to be addressed.

The Vineland Adaptive Behavior Scales: supplementary norms for individuals with autism.

Vineland Adaptive Behavior Scales Special Population norms are presented for four groups of individuals with autism: (a) mute children under 10 years of age; (b) children with at least some verbal skills under 10 years of age; (c) mute individuals who are 10 years of age or older; and (d) individuals with at least some verbal skills who are 10 years of age or older. The sample included 684 autistic individuals ascertained from cases referred for the DSM-IV autism/PDD field trial collaborative study and five university sites with expertise in autism. Young children had higher standard scores than older individuals across all Vineland domains. In the Communication domain, younger verbal children were least impaired, older mute individuals most impaired, and younger mute and older verbal individuals in the midrange. Verbal individuals achieved higher scores in Daily Living Skills than mute individuals. The expected profile of a relative weakness in Socialization and relative strength in Daily Living Skills was obtained with age-equivalent but not standard scores. Results high-light the importance of employing Vineland special population norms as well as national norms when evaluating individuals with autism.

A normed study of face recognition in autism and related disorders.

Although the interpretation of studies of face recognition in older children, adolescents, and adults with autism is complicated by the fact that participating samples and adopted methodologies vary significantly, there is nevertheless strong evidence indicating processing peculiarities even when task performance is not deficient. Much less is known about face recognition abilities in younger children with autism. This study employed a well-normed task of face recognition to measure this ability in 102 young children with autism, pervasive developmental disorder not otherwise specified (PDDNOS), and non-PDD disorders (mental retardation and language disorders) matched on chronological age and nonverbal mental age, and in a subsample of 51 children divided equally in the same three groups matched on chronological age and verbal mental age. There were pronounced deficits of face recognition in the autistic group relative to the other nonverbally matched and verbally matched groups. Performance on two comparison tasks did not reveal significant differences when verbal ability was adequately controlled. We concluded that young children with autism have face recognition deficits that cannot be attributed to overall cognitive abilities or task demands. In contrast to controls, there was a lower correlation between performance on face recognition and nonverbal intelligence, suggesting that in autism face recognition is less correlated with general cognitive capacity. Contrary to our expectation, children with PDDNOS did not show face recognition deficits.

Changes in distribution of the phases of mitosis in human tumor xenografts following drug treatment.

Distribution of individual mitotic phases in different human xenografts on nude mice showed significant changes after treatment with a range of drugs when compared with untreated controls. The total amount of mitoses in prophase significantly decreased in all responsive tumors while those in all other phases increased but in a very variable degree. There was some correlation in between the range of the mitotic phase distribution changes and the degree of tumor response to treatment.

Relationship between melanogenesis, proliferative activity and response to chemotherapy of human melanoma xenografts.

Wide range of different drugs used in the cytotoxicity studies in an amelanotic human melanoma xenograft on nude mice showed a clear inverse relationship between melanogenesis and proliferation. Decreasing rates in proliferative activity estimated by mitotic answer expressed by phase distribution changes as well as by the tumor volume response to drug treatment were in direct relationship with increasing rates in the degree of melanogenesis expressed in percentage of melanin containing cells in histological specimens.

K-ABC profiles in children with fragile X syndrome, Down syndrome, and nonspecific mental retardation.

Etiology-specific profiles of intellectual abilities were compared in three groups of males with mental retardation using the Kaufman Assessment Battery for Children (K-ABC). Subjects included 10 males with fragile X syndrome, 10 with Down syndrome, and 10 with nonspecific mental retardation who were equated on both mental and chronological age. Across all three groups, sequential processing was lower than simultaneous processing or achievement, and particular subtests (e.g., Gestalt Closure) were relative strengths. Although boys with Down syndrome showed less extreme patterns of domain strengths and weaknesses, they showed a significant strength in the Sequential Processing Hand Movements subtest. In contrast, the Hand Movements subtest was lowest of all K-ABC subtests for males with fragile X syndrome. Implications were discussed for more fine-tuned research and intervention efforts.

Salivary monomorphic adenomas of dermal analogue type: report of two cases.

Two cases of monomorphic adenoma, dermal analogue type, are presented illustrating fine-needle aspiration cytology and subsequent histopathology. Aspiration findings were similar in both cases, demonstrating aggregates of mildly disorganised small regular epithelial cells bordered by a thick rim of basement membrane material. In the first case seen, there was a prominent lymphoid component which gave rise to the false suspicion that the lesion was lymphoepithelial in nature. The cytological features of this tumour are characteristic, however, and their recognition is important to enable distinction from malignancy (e.g., adenoid cystic carcinoma), other benign neoplasms (e.g., plemorphic adenoma), and non-neoplastic conditions.

Sendai virus in nude and germ-free rats.

The pathogenesis of Sendai virus infection was studied in athymic and AGUS rats. The infection was more severe in the athymic rats and caused considerable clinical disease. Virus was shown to replicate in the bronchial epithelium and persisted in athymic rats for the duration of the experiment (32 days). The characteristic changes of necrosis of the bronchial epithelium and subsequent hyperplasia also persisted in this group and was accompanied by quite extensive interstitial pneumonitis. The virus failed to evoke an antibody response in the athymic rats.

Murine coronaviruses: the histopathology of disease induced by intranasal inoculation.

Mice inoculated intranasally with murine coronaviruses (mouse hepatitis viruses) were killed daily for seven days. Lung and liver sections stained by the immunoperoxidase technique indicated that with three of the four strains examined viral localisation and replication in the lung preceded that found in the liver. Thus, infection by the respiratory route may be of importance in the transmission of these viruses.