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Using a population-based sampling strategy, the National Institutes of Health (NIH) Magnetic Resonance Imaging Study of Normal Brain Development compiled a longitudinal normative reference database of neuroimaging and correlated clinical/behavioral data from a demographically representative sample of healthy children and adolescents aged newborn through early adulthood. The present paper reports brain volume data for 325 children, ages 4.5-18 years, from the first cross-sectional time point. Measures included volumes of whole-brain gray matter (GM) and white matter (WM), left and right lateral ventricles, frontal, temporal, parietal and occipital lobe GM and WM, subcortical GM (thalamus, caudate, putamen, and globus pallidus), cerebellum, and brainstem. Associations with cross-sectional age, sex, family income, parental education, and body mass index (BMI) were evaluated. Key observations are: 1) age-related decreases in lobar GM most prominent in parietal and occipital cortex; 2) age-related increases in lobar WM, greatest in occipital, followed by the temporal lobe; 3) age-related trajectories predominantly curvilinear in females, but linear in males; and 4) small systematic associations of brain tissue volumes with BMI but not with IQ, family income, or parental education. These findings constitute a normative reference on regional brain volumes in children and adolescents.

Two neonates were identified at age 48 h by expanded newborn screening, with abnormal methionine and tyrosine concentrations, which were confirmed on repeat samples. Evidence of previously unsuspected liver disease was found at recall, and there was radiological and biochemical evidence of severe liver disease with hepatic synthetic failure. After inborn errors of metabolism (IEMs) were excluded, both were considered to have neonatal haemochromatosis, on the basis of raised ferritin, iron saturation, and very high α-fetoprotein and confirmed by a mildly hyperferritinaemic sibling in the first case, and raised ferritin and iron saturation in the second. However, it was not feasible to obtain tissue confirmation as the requirement for early therapy precluded biopsy. The babies were treated with antioxidants and iron-chelating agents, and the coagulopathy and hypoalbuminaemia were corrected. Both made a complete recovery and remain well after follow-up. Newborn screening programmes could consider advising clinicians, when tyrosine and methionine values are elevated, that once IEMs are excluded liver disease from other causes must be sought. Neonatal haemochromatosis is an example of one such disease that is potentially treatable.

Children with congenital hydrocephalus, children with attention deficit-hyperactivity disorder, and normal controls were evaluated with measures of focused attention (Visual Orienting and Detection Task), sustained attention (continuous performance test), and attention shifting (Wisconsin Card Sorting Test). Components from these tasks have been linked to attention systems mediated by anterior or posterior brain networks. Children with congenital hydrocephalus showed an inability to focus and shift attention, which specifically implicated impairment of the disengage and move components of the posterior brain attention system. Children with attention deficit-hyperactivity disorder displayed the expected performance patterns on measures of focused attention once their difficulties with sustained attention were taken into account. However, they showed problems with shifting and sustaining attention, which are commonly associated with the anterior brain attention system.

A paired-associate learning (PAL) test was administered to 22 community volunteers without disruptive disorders and 197 children (7.5-13.5 years-old) presenting with the inattentive and combined subtypes of attention-deficit/hyperactivity disorder (ADHD) either in combination with or without oppositional defiant disorder (ODD). Participants were screened for learning disorders. In comparison to non-ADHD participants, children with ADHD achieved worse PAL and made errors rated as more acoustically and less semantically similar to the correct paired associates. These deficits were not related to hyperactivity-impulsivity or comorbid ODD. These results suggest that ADHD children are less competent at PAL and use less efficient learning strategies than their non-ADHD peers.

We previously reported on cognitive and respiratory factors in a series of infants with achondroplasia (ACH). We now present the results of neuropsychological evaluation and magnetic resonance imaging in 16 school-age children with ACH, 7 of whom had been included as infants in our previous report. We examined the neuroanatomic and cognitive status of this sample, as well as the predictive stability of the prior infant assessment. Seventeen normally developing children of average stature and 21 preterm children with arrested (compensated, unshunted) hydrocephalus constituted the comparison groups. Brain volumes of children with ACH were significantly larger than those of the comparison groups. In addition, children with ACH exhibited kinking of the medulla and neuroanatomic abnormalities consistent with arrested hydrocephalus, including enlarged ventricles and hypoplasia of the corpus callosum. Cognitive abilities at school age were average, although mild deficits were seen on visual-spatial tasks, similar to those obtained by the hydrocephalic comparison group. Only gross motor coordination deficits distinguished the ACH group from the hydrocephalic controls. Infant assessment overestimated later school-age IQ scores in those infants with ACH who scored above average. These findings point to generally preserved cognitive skills in selected children with ACH at early school age, although children with ACH should be evaluated individually as they are at risk for cognitive, academic, and motor deficits.

Children with arrested, shunted, and no hydrocephalus were compared on verbal and nonverbal memory tasks assessing multiple components of memory. A gradient of severity was hypothesized, with the shunted hydrocephalus group expected to exhibit the most significant memory impairments and the arrested group expected to perform more poorly than children with no hydrocephalus. Etiologies of prematurity, spina bifida, and aqueductal stenosis were represented by 157 participants. Results supported the hypothesis; the shunted hydrocephalus group performed poorer on all memory measures. Differences for the arrested group were less frequently statistically significant relative to children with no hydrocephalus. Irrespective of etiology, the shunted hydrocephalus group exhibited a pattern of performance suggestive of encoding and retrieval deficits on both verbal and nonverbal tasks, showing a pervasive disturbance of memory processes.

Our objective was to review the Australasian experience of X-linked adrenoleukodystrophy (ALD), to compare the spectrum of disease seen in Australasia with previously published data from elsewhere, and to assess the reliability of carrier testing. Study design was a retrospective review of records collected over a 15-year period, the setting was an international referral laboratory for the study of metabolic disease, and the subjects were all known cases of ALD diagnosed in Australia and New Zealand between 1981 and 1996 and their families. We estimate that the combined incidence of ALD and its variants in Australasia is at least 1.6 per 100,000. Of 95 affected males, 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison's disease only, and 5 remained asymptomatic when last examined. However, the distribution of phenotypes among newly diagnosed patients has changed substantially over the last 15 years, with cerebral forms of the disease forming a decreasing proportion of new diagnoses. The measurement of plasma very long chain fatty acids (VLCFAs) alone detects 93% of women who can be proven to be carriers. The addition of genetic linkage studies or assay of VLCFAs in cultured fibroblasts improved this detection rate to the point that there were no obligate carriers who could not be detected using a combination of two or more techniques.

To further investigate the usefulness of 3 purported measures of executive function (EF) in head injured children, we administered the Twenty Questions Test (TQT), Tower of London (TOL), and the Wisconsin Card Sorting Test (WCST) to 151 children who had sustained a closed head injury (CHI) of varying severity about 3 years earlier. In addition, we tested 89 normal controls. Fifty-seven of the patients were included in a longitudinal study that compared performance at 3 months and 36 months. All of the head injured children underwent magnetic resonance imaging for investigational purposes. Severity of CHI, as defined by the lowest Glasgow Coma Scale (GCS) score, affected performance on all 3 EF measures. Focal lesion volume incremented prediction of performance on TOL and WCST, but not TQT. Moderate intercorrelations of the test variables were obtained. Although all three EF measures depicted changes in performance over 3 years, a ceiling effect detracted from the sensitivity of the TOL to the impact of CHI on development. Implications of the findings for clinical applications are discussed.

Heparan sulfate proteoglycans have been implicated in the presentation of a number of secreted signaling molecules to their signal-transducing receptors. We have characterized a gene trap mutation in the gene encoding a heparan sulfate biosynthetic enzyme, heparan sulfate 2-sulfotransferase (HS2ST). Transgenic mice were generated from embryonic stem cells harboring this insertion.lacZ reporter gene activity in heterozygous embryos demonstrates that the gene is expressed differentially during embryogenesis, presumably directing dynamic changes in heparan sulfate structure. Moreover, mice homozygous for the Hs2st gene trap allele die in the neonatal period, exhibiting bilateral renal agenesis and defects of the eye and the skeleton. Analysis of kidney development in Hs2st mutants reveals that the gene is not required for two early events—ureteric bud outgrowth from the Wolffian duct and initial induction of Pax-2 expression in the metanephric mesenchyme. It is required, however, for mesenchymal condensation around the ureteric bud and initiation of branching morphogenesis. Because 2-O-sulfation has been shown to influence the functional interactions of ligands with heparan sulfate in vitro, we discuss the possibility that the Hs2st mutant phenotype is a consequence of compromised interactions between growth factors and their signal-transducing receptors. These data provide the first genetic evidence that the regulated synthesis of differentially glycosylated proteoglycans can affect morphogenesis during vertebrate development.

This study linked 2 experimental paradigms for the analytic study of reading that heretofore have been used separately. Measures on a lexical decision task designed to isolate phonological effects in the identification of printed words were examined in young adults. The results were related to previously obtained measures of brain activation patterns for these participants derived from functional magnetic resonance imaging (fMRI). The fMRI measures were taken as the participants performed tasks that were designed to isolate orthographic, phonological, and lexical-semantic processes in reading. Individual differences in the magnitude of phonological effects in word recognition, as indicated by spelling-to-sound regularity effects on lexical decision latencies and by sensitivity to stimulus length effects, were strongly related to differences in the degree of hemispheric lateralization in 2 cortical regions.

In view of the pathophysiology and biomechanics of severe closed head injury (CHI) in children, we postulated that the frontal lobes sustain diffuse injury, even in the absence of focal brain lesions detected by magnetic resonance imaging (MRI). This study quantitated the morphological effects of CHI on the frontal lobes in children who sustained head trauma of varying severity. The MRI findings of 14 children who had sustained severe CHIs (Glasgow Coma Scale score ofor = 8) were compared with the findings in a matched group of 14 children having sustained mild head injuries (Glasgow Coma Scale score of 13-15). The patients ranged in age from 5 to 15 years at the time of their MRIs, which were acquired at least 3 months postinjury. MRI findings revealed no focal areas of abnormal signal in the frontal lobes. Volumetric analysis disclosed that the total prefrontal cerebrospinal fluid increased and the gray matter volume decreased in the patients with severe CHI, relative to the mildly injured comparison group. Gray matter volume was also reduced in the orbitofrontal and dorsolateral regions of the brains of children with severe CHI, relative to the children who sustained mild head trauma. These volumetric findings indicate that prefrontal tissue loss occurs after severe CHI in children, even in the absence of focal brain lesions in this area. Nearly two-thirds of the children who sustained severe CHIs were moderately disabled after an average postinjury interval of 3 years or more, whereas 12 of the 14 patients with mild CHIs attained a good recovery (2 were moderately disabled) by the time of study.(ABSTRACT TRUNCATED AT 250 WORDS)

The direct actions of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1(7-36)amide and insulin on lipoprotein lipase activity in explants of rat epididymal adipose tissues were investigated. Lipoprotein lipase was extracted into the incubation medium by heparin release of lipoprotein lipase and measured by fatty acid release from a glyceroltriolein emulsion. Insulin and glucose-dependent insulinotropic polypeptide caused a significant stimulation of lipoprotein lipase activity over a dose range of 0.25-4 nmol/L and 4-8 nmol/L, respectively. Explants incubated in the presence of both insulin and glucose-dependent insulinotropic polypeptide (at 0.5 and 4 nmol/L, respectively) showed levels of lipoprotein lipase activity significantly greater than that seen with either hormone alone. Neither insulin- nor glucose-dependent insulinotropic polypeptide-stimulated lipoprotein lipase was modified by the presence of the antibiotic actinomycin-D in the incubation medium, indicating that these two hormones exert their actions on the pre-existing cellular pool of lipoprotein lipase. Glucagon-like polypeptide-1(7-36)amide, over a dose range of 1-8 nmol/L, did not stimulate lipoprotein lipase activity. This study indicates that glucose-dependent insulinotropic polypeptide, in addition to stimulating insulin secretion, has a direct biological action on adipose tissue and in vivo, together with insulin, may promote lipoprotein lipase activity postprandially.

Neurobehavioral outcome after craniocerebral gunshot wounds was evaluated in a prospective, 3-year, longitudinal follow-up of a consecutive case series of 13 children and adolescents. The younger group was composed of seven children, ages 1.5 to 4 years, and the older group contained six children, ages 5 to 14. Outcome measures included the Glasgow Outcome Scale and neuropsychological assessment of intelligence, language, motor, memory, attention, academic achievement, and adaptive behavior. Glasgow Outcome Scale scores at baseline indicated moderate and severe disabilities in 69 and 23%, respectively. At the 3-year follow-up, 85% had moderate disabilities but only 8% were severely disabled. Significant and persistent neurobehavioral deficits varied with developmental level at the time of cerebral insult. Intellectual functioning was clearly more impaired in children younger than 5 years of age at the time of injury than in older children. Cognitive and motor factors were most closely related to deficits in the younger group. Disability in older children and adolescents was associated with impaired attention, adaptive behavior, and behavioral disturbance. Disabilities appear to be at least as severe in our sample after cerebral gunshot wounds as in our studies of severe pediatric closed-head injury. At the time of follow-up, younger children sustaining gunshot wounds had slightly lower intelligence quotient scores and similar receptive language, expressive language, and gross motor scores compared with children with severe closed-head injury. The older gunshot wound patients were significantly more impaired than patients with severe closed-head injuries on measures of adaptive behavior and attention.(ABSTRACT TRUNCATED AT 250 WORDS)

Mutation or deletion of the PAX6 gene underlies many cases of aniridia. Three lines of evidence now converge to implicate PAX6 more widely in anterior segment malformations including Peters' anomaly. First, a child with Peters' anomaly is deleted for one copy of PAX6. Second, affected members of a family with dominantly inherited anterior segment malformations, including Peters' anomaly are heterozygous for an R26G mutation in the PAX6 paired box. Third, a proportion of Sey/+ Smalleye mice, heterozygous for a nonsense mutation in murine Pax-6, have an ocular phenotype resembling Peters' anomaly. We therefore propose that a variety of anterior segment anomalies may be associated with PAX6 mutations.

The Children's Orientation and Amnesia Test (COAT) was developed to assess cognition serially during the early stage of recovery from traumatic brain injury in children and adolescents. The norms for the COAT, which is composed of 16 items evaluating general orientation, temporal orientation, and memory, were defined from data obtained from 146 children aged 3 to 15 years. In 37 patients with head injuries, the duration of posttraumatic amnesia, as indicated by the number of days COAT scores were in the impaired range, was significantly related to both verbal and nonverbal memory at the baseline and 6 and 12 months after injury. COAT scores were a better predictor of verbal and nonverbal memory performance than the Glasgow Coma Scale score at 6 and 12 months after the injury. This study shows that the COAT has adequate reliability and validity as a measure of the duration of posttraumatic amnesia in children and adolescents.

We hypothesized that results of previous investigations indicating an increased prevalence of reading disability in boys compared with girls reflected a bias in subject selection. In an epidemiologic sample of 215 girls and 199 boys, we identified two groups of reading-disabled children: research identified and school identified. Results indicated no significant differences in the prevalence of reading disability in research-identified boys compared with research-identified girls in either second (17[8.7%] of 196 boys; 15[6.9%] of 216 girls) or third grade (18[9.0%] of 199 boys; 13[6.0%] of 215 girls). In contrast, school identification resulted in the classification of 27 (13.6%) of 198 boys and seven (3.2%) of 216 girls in second grade and 20 (10.0%) of 199 boys and nine (4.2%) of 215 girls in third grade. Our data indicate that school-identified samples are almost unavoidably subject to a referral bias and that reports of an increased prevalence of reading disability in boys may reflect this bias in ascertainment. These findings caution against relying solely on schools for identification of reading-disabled children.

This study provides a longitudinal follow-up of the behavioral adjustment of 45 children with mild, moderate, and severe closed head injuries. Two measures of behavioral adjustment, the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales (VABS), were obtained from a parent at the time of injury and at 6 and 12 months postinjury. The severely injured children obtained significantly poorer VABS scores than children with mild and moderate injuries over the year-long follow-up. In addition, on the CBCL, severely injured children had more school problems and engaged in fewer social activities than mild and moderately injured children. These results show that severe head injury in children was associated with declines in adaptive functioning, whereas scores for children with mild and moderate injuries did not differ, nor did they deviate from average levels at any follow-up interval.

Nine probes were isolated from a human chromosome 1 enriched library and mapped to regions of chromosome 1 using somatic cell hybrid lines. One clone, LR67, which mapped to 1q12----q23 detected a BglI RFLP. This probe, as well as 4 other known chromosome 1 markers, alpha-spectrin, Factor XIIIB, DR10 and DR78, were used for linkage studies in 15 Charcot-Marie-Tooth disease (CMT1) families. Close linkage of CMT1 to any of the 5 markers was not indicated. Total lod scores excluded linkage of CMT1 to LR67 and to DR10 at 5 cM or less, to DR78 at 10 cM or less, alpha-spectrin at 15 cM or less and Factor XIIIB at 20 cM or less. Possible linkage, however, was shown between LR67 and CMT1 at a distance of 30 cM. Also linkage at a distance of 5 cM was detected between this probe and alpha-spectrin.

Details are given of a balanced 21q22q Robertsonian translocation ascertained through infertility in a phenotypically normal male. Chromosome analyses on the proband and his parents showed that the translocation arose as a new mutation. The patient was oligospermic and had a high frequency of morphological abnormalities in his spermatozoa. Meiotic investigations showed a chain trivalent in all primary spermatocytes examined at diakinesis/metaphase I. The testicular histology was normal.

The effects of endogenous gonadal hormones on the regulation of body composition and energy retention have been investigated under conditions of controlled food intake. Male and female rats were fed the same amount from weaning to 82 days of age. The carcases of males contained more protein, less lipid and yielded more ash than females, but they had the same amount of total energy in their carcases as females. In a second experiment, male rats were sham-operated or castrated at 19 days and then fed equal amounts from weaning. At 40 days, intact and castrated rats did not differ in total carcase energy content nor in carcase composition. At 82 days the carcases of intact rats had more protein but had retained the same amount of energy as castrated rats. By 131 days, the difference in protein content was larger and intact rats had less carcase lipid, less carcase energy and gave less ash than castrated rats. At the same age and with a similar food intake, the differences in carcase composition between intact males and females were considerably larger than between intact and castrated males. In a third experiment, male rats were sham-operated or castrated at 1 day post partum and fed the same amount as in the second experiment from weaning to 82 days. Both sham-castrated and castrated rats grew less well than rats operated on at 19 days. The differences in carcase composition between intact and castrated rats were in the same direction but of greater magnitude than in rats operated at the later age. In a fourth experiment the effects on body compositon and energy retention of sham-operation, castration or immunization to LH-releasing hormone (LHRH) at weaning were compared in male rats fed the same amount from weaning to 131 days. Intact rats retained less carcase energy, less lipid and produced less ash than castrated and LHRH-immunized animals. Castrated and LHRH-immunized rats did not differ in carcase composition or amount of energy retained. It is concluded that (1) endogenous sex steroids affect growth and carcase composition independently of food intake, (2) the characteristic carcase composition of the female rat is largely due to the presence of ovarian steroids rather than lack of testicular steroids, (3) in the absence of increased food intake the effects of testicular steroids upon growth and energy expenditure are small but similar to those found in animals with free access to food, (4) the long-terms effects of perinatal exposure to testicular steroids upon growth and carcase composition are not only a consequence of changed food intake and (5) surgical castration and functional castration, induced by LHRH auto-immunization, produce the same effects on carcase composition. J. Endocr. (1986) 110, 97–102

Trisomy 8, in mosaic or non-mosaic form is an extremely rare chromosomal condition in man. Liveborn subjects usually present with mental retardation, bone and joint anomalies and a variety of other physical anomalies. The mental retardation associated with the condition is, however, usually moderate compared to that found in other viable human autosomal trisomic conditions. The present report describes a trisomy 8 mosaic male subject with normal IQ and near-normal phenotype, ascertained through infertility. Chromosome studies on peripheral blood lymphocytes reveal a pure trisomy 8 constitution; cultured skin fibroblasts show 46,XY/47,XY+8 mosaicism. At meiosis, the extra No. 8 chromosome is missing from the germ line. The testicular histology indicates a germ cell maturation arrest in many spermatocytes and the patient is severely oligospermic. Biochemical studies to assay levels of glutathione reductase, a red cell enzyme, the gene for which resides in chromosome 8, show increased levels in the trisomy 8 patient compared with controls.

A systematic survey of 1599 male patients attending a subfertility clinic has shown that 2.2% were chromosomally abnormal. This frequency was approximately five times higher than that found among the normal male population. The majority of chromosome abnormalities (at least in chromatin-negative males) appeared to be exerting their effect on male fertility through disturbance of spermatogenesis. The contribution made by chromosome abnormalities causing recurrent abortion in wives was negligible. The possible reasons underlying impairment of spermatogenesis in man are discussed in relation to the findings in other species, and the suggestion that some elimination of chromosomally unbalanced gametes occurs from the human male germ line is proposed.

Intact obese rats were hyperinsulinaemic, had higher rates of whole-body fatty acid synthesis, higher activities of hepatic acetyl-CoA carboxylase and tyrosine aminotransferase and a higher hepatic glycogen concentration than intact lean animals. Adrenalectomy abolished all these factors of the obese phenotype. Treatment of adrenalectomized rats with corticosterone for 24 h increased the rate of whole-body fatty acid synthesis to the same extent in both phenotypes, but caused a larger increase in glycogen concentration, tyrosine aminotransferase activity and plasma insulin concentration in obese rats.

The effects of episodic infusion of testosterone into the vascular system on energy expenditure, nitrogen retention and whole body protein synthesis (determined from [1-14C]leucine kinetics) were studied in castrated male lambs under conditions of controlled food intake. Comparisons were made between a 10-day control period and a 10-day treatment period for each lamb. Infusion of testosterone produced a significant increase in heat production, but the magnitude (198 kJ/day, +2·5% was less than the differences in energy expenditure expected between entire and castrated male ruminants. The retention of nitrogen improved by 1·24 g/day ( + 22%) in response to the administration of androgen, and this was accompanied by a decrease in amino acid oxidation. Total protein synthesis also declined, and the anabolic nature of testosterone supply must, therefore, be effected through a reduction in the breakdown of protein, the mechanism being similar to that proposed for certain anabolic steroids and the β-agonist, clenbuterol. Contrary to other reports, the presence of testosterone had no effect on the plasma concentration of GH. J. Endocr. (1987) 115, 439–445

Sacciform cells containing an acidophilic, proteinaceous secretion, were identified in the epidermis of the brown trout and Arctic char. This cell type increased in number during the chronic stages of infestation by the ectoparasitic flagellate, Ichthyobodo sp., in immature brown trout, and decreased during sexual maturation in male brown trout and char. It is suggested that the salmonid sacciform cell produces a secretion which protects the fish against infestation or damage by skin parasites.

Cytological evidence for the existence of a Y-autosomal rearrangement in meiotic cells of Sxr mice has been sought. At peachytene, in silver-stained light microscope spread preparations of XY, Sxr/+ and XO, Sxr/+ spermatocytes, evidence for pairing or association between a possible Y-bearing segment of a specific autosome and a sex chromosome could not, however, be found. Such sex chromosome-autosome associations as were seen were non-specific in nature, and occurred no more often in Sxr mice than in controls.

The rate of whole body fatty acid synthesis was measured in immature (18- and 25-day-old) lean and obese male Zucker rats. The effect of stress and diurnal variation on the rate of fatty acid synthesis was also determined in 25-day-old animals. In addition, the intake of fatty acid from the diet was also determined. At 16 and 18 days the carcase of the obese rat contained significantly more lipid than its lean counterpart. In neither phenotype was there any significant lipid deposition from 18 to 23 days. Over the period 23 to 27 days the obese rat deposited approximately six times more lipid than its lean counterpart. Consistent with this finding is the observation that at 25 days the obese rat synthesized at least four to five times more fatty acid than its lean littermate. There was no phenotypic difference in the rate of fatty acid synthesis at 18 days. It is suggested that the young obese rat becomes obese before weaning because of a reduced oxidation, and hence increased storage, of dietary fatty acid. After weaning, although this unusual partition persists, hyperlipogenesis is the main cause of the further development of obesity.