Teens with heavy prenatal cocaine exposure respond to experimental social provocation with escape not aggression.

Preclinical data show that, compared to no exposure, prenatal cocaine exposure (PCE) has age-dependent effects on social interaction and aggression. The aim of this clinical study was to determine how heavy/persistent PCE--after controlling for other prenatal drug exposures, sex and postnatal factors--predicts behavioral sensitivity to provocation (i.e., reactive aggression) using a well-validated human laboratory model of aggression. African American teens (mean=14.2 years old) with histories of heavy/persistent PCE (maternal cocaine use ≥ 2 times/week during pregnancy, or positive maternal or infant urine/meconium test at delivery; n=86) or none/some exposure (NON: maternal cocaine use < 2 times/week during pregnancy; n=330) completed the Point Subtraction Aggression Paradigm. In this task, teens competed in a computer game against a fictitious opponent. There were three possible responses: (a) earn points, to exchange for money later; or (b) "aggress" against the fictitious opponent by subtracting their points; or (c) escape temporarily from point subtraction perpetrated by the fictitious opponent. The PCE group responded significantly more frequently on the escape option than the NON group, but did not differ in aggressive or money-earning responses. These data indicate that PCE-teens provoked with a social stressor exhibit a behavioral preference for escape (negative reinforcement) than for aggressive (retaliatory) or appetitive (point- or money-reinforced) responses. These findings are consistent with preclinical data showing that social provocation of adolescent or young adult offspring after PCE is associated with greater escape behavior, inferring greater submission, social withdrawal, or anxiety, as opposed to aggressive behavior.

Characteristics of abnormal diffusivity in normal-appearing white matter investigated with diffusion tensor MR imaging in tuberous sclerosis complex.

BACKGROUND AND PURPOSE: Although patients with tuberous sclerosis complex (TSC) manifest various structural abnormalities, we hypothesized that white matter (WM) structures that appear normal on conventional MR imaging may be accompanied by microstructural changes, such as gliosis and myelinization defects. Our objective was to determine in vivo whether there was evidence for WM microstructural changes by using diffusion tensor imaging (DTI). MATERIALS AND METHODS: We used DTI to evaluate diffusivity and anisotropy in normal-appearing WM (NAWM) of 6 children with TSC and 12 age-matched control subjects. The anterior and posterior limbs of the internal capsule, the external capsule, and the genu and splenium of the corpus callosum were assessed. We hypothesized that previously reported DTI abnormalities of NAWM in patients with TSC may not be equal in all diffusion directions as measured by the major, middle, and minor eigenvalues. RESULTS: When combining NAWM regions in patients with TSC, we observed a significant increase in mean diffusivity (P = .003) and a decrease in anisotropy (P = .03) compared with those of controls. However, the increase in diffusivity was more pronounced in directions orthogonal to the axons measured by the minor and middle eigenvalues (P = .005) than by the major eigenvalue (P = .02). CONCLUSION: Our findings revealed a decrease in anisotropy and an increase in longitudinal and radial diffusivities in NAWM beyond the location of TSC lesions seen on conventional MR imaging. The axonal microstructural changes suggested by our study may be related to changes in myelin packing due to giant cells accompanied by gliosis and myelination defects known to occur in TSC WM.

Prolonged vigabatrin treatment modifies developmental changes of GABA(A)-receptor binding in young children with epilepsy.

PURPOSE: To determine whether prolonged treatment with vigabatrin (VGB), an antiepileptic drug (AED) that acts by elevating brain gamma-aminobutyric acid (GABA) levels, interferes with age-related changes of in vivo GABA(A)-receptor binding in children with epilepsy. METHODS: Using [11C]flumazenil (FMZ)-positron emission tomography (PET) imaging, 15 children (aged 1-8 years) with medically intractable epilepsy were studied. Seven of these children were treated with VGB (1,000-2,500 mg/day) for > or =3 months before the FMZ-PET study. The remaining eight patients were medicated with other drugs that are known not to act directly on the GABAergic system. Absolute quantification of PET data was performed by using the volume of distribution (VD) of FMZ in brain tissue representing FMZ ligand binding. RESULTS: After controlling for age, hemispheric FMZ VD values were significantly lower in children treated with VGB as compared with the non-VGB group (p = 0.012). Regional FMZ VD values of the VGB-treated patients were significantly lower in all cortical regions and the cerebellum, whereas the difference was not significant in the thalamus and basal ganglia. No significant drug effect or drug-by-region interaction could be determined when the patients were separated according to treatment with carbamazepine (p = 0.97) or valproate (p = 0.55). CONCLUSIONS: VGB induces a decrease in GABA(A)-receptor binding in the cortex and cerebellum of the developing epileptic brain. A similar effect of other drugs and substances of abuse targeting the GABAergic system may be hypothesized. Because of the important role of the GABAergic system in developmental plasticity, the reversibility and functional consequences of this age-specific drug effect should be further studied.

Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction.

OBJECTIVE: To examine the relationship between autism and epilepsy in relation to structural and functional brain abnormalities in children with tuberous sclerosis complex (TSC). METHODS: Children with TSC and intractable epilepsy underwent MRI as well as PET scans with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and alpha-[(11)C]methyl-L-tryptophan (AMT). Based on the results of Autism Diagnostic Interview-Revised, Gilliam Autism Rating Scale, and overall adaptive behavioral composite (OABC) from Vineland Adaptive Behavior Scale, subjects were divided into three groups: autistic (OABC < 70; n = 9), mentally-retarded nonautistic (OABC < 70; n = 9), and relatively normal intelligence (OABC > or = 70; n = 8). RESULTS: PET studies showed that the autistic group had decreased glucose metabolism in the lateral temporal gyri bilaterally, increased glucose metabolism in the deep cerebellar nuclei bilaterally, and increased AMT uptake in the caudate nuclei bilaterally, compared to the mentally-retarded nonautistic group. In addition, a history of infantile spasms and glucose hypometabolism in the lateral temporal gyri were both significantly associated with communication disturbance. Glucose hypermetabolism in the deep cerebellar nuclei and increased AMT uptake in the caudate nuclei were both related to stereotypical behaviors and impaired social interaction, as well as communication disturbance. CONCLUSIONS: These results suggest that generalized epilepsy in early life and functional deficits in the temporal neocortices may be associated with communication delays, and that functional imbalance in subcortical circuits may be associated with stereotypical behaviors and impaired social interaction in children with TSC.

Prenatal alcohol exposure and childhood behavior at age 6 to 7 years: I. dose-response effect.

OBJECTIVE: Moderate to heavy levels of prenatal alcohol exposure have been associated with alterations in child behavior, but limited data are available on adverse effects after low levels of exposure. The objective of this study was to evaluate the dose-response effect of prenatal alcohol exposure for adverse child behavior outcomes at 6 to 7 years of age. METHODS: Beginning in 1986, women attending the urban university-based maternity clinic were routinely screened at their first prenatal visit for alcohol and drug use by trained research assistants from the Fetal Alcohol Research Center. All women reporting alcohol consumption at conception of at least 0.5 oz absolute alcohol/day and a 5% random sample of lower level drinkers and abstainers were invited to participate to be able to identify the associations between alcohol intake and child development. Maternal alcohol, cigarette, and illicit drug use were prospectively assessed during pregnancy and postnatally. The independent variable in this study, prenatal alcohol exposure, was computed as the average absolute alcohol intake (oz) per day across pregnancy. At each prenatal visit, mothers were interviewed about alcohol use during the previous 2 weeks. Quantities and types of alcohol consumed were converted to fluid ounces of absolute alcohol and averaged across visits to generate a summary measure of alcohol exposure throughout pregnancy. Alcohol was initially used as a dichotomous variable comparing children with no prenatal alcohol exposure to children with any exposure. To evaluate the effects of different levels of exposure, the average absolute alcohol intake was relatively arbitrarily categorized into no, low (>0 but <0.3 fl oz of absolute alcohol/day), and moderate/heavy (>/=0.3 fl oz of absolute alcohol/day) for the purpose of this study. Six years later, 665 families were contacted. Ninety-four percent agreed to testing. Exclusions included children who missed multiple test appointments, had major congenital malformations (other than fetal alcohol syndrome), possessed an IQ >2 standard deviations from the sample mean, or had incomplete data. The Achenbach Child Behavior Checklist (CBCL) was used to assess child behavior. The CBCL is a parent questionnaire applicable to children ages 4 to 16 years. It is widely used in the clinical assessment of children's behavior problems and has been extensively used in research. Eight syndrome scales are further grouped into Externalizing or undercontrolled (Aggressive and Delinquent) behavior and Internalizing or overcontrolled (Anxious/Depressed, Somatic Complaints, and Withdrawn) behaviors. Three syndromes (Social, Thought, and Attention Problems) fit neither group. Higher scores are associated with more problem behaviors. Research assistants who were trained and blinded to exposure status independently interviewed the child and caretaker. Data were collected on a broad range of control variables known to influence childhood behavior and/or to be associated with prenatal alcohol exposure. These included perinatal factors of maternal age, education, cigarette, cocaine, and other substances of abuse and the gestational age of the baby. Postnatal factors studied included maternal psychopathology, continuing alcohol and drug use, family structure, socioeconomic status, children's whole blood lead level, and exposure to violence. Data were collected only from black women as there was inadequate representation of other racial groups. STATISTICAL ANALYSES: Statistical analyses were performed using the SPSS statistical package. Frequency distribution, cross-tabulation, odds ratio, and chi(2) tests were used for analyzing categorical data. Continuous data were analyzed using t tests, analyses of variance (ANOVAs) with posthoc tests, and regression analysis. RESULTS: Testing was available for 501 parent-children dyads. Almost one fourth of the women denied alcohol use during pregnancy. Low levels of alcohol use were reported in 63.8% and moderate/heavy use in 13% of pregnancies. Increasing prenatal alcohol exposure was associated with lower birth weight and gestational age, higher lead levels, higher maternal age, and lower education level, prenatal exposure to cocaine and smoking, custody changes, lower socioeconomic status, and paternal drinking and drug use at the time of pregnancy. Children with any prenatal alcohol exposure were more likely to have higher CBCL scores on Externalizing (Aggressive and Delinquent) and Internalizing (Anxious/Depressed and Withdrawn) syndrome scales and the Total Problem Score. The odds ratio of scoring in the clinical range for Delinquent behavior was 3.2 (1.3-7.6) in children with any prenatal exposure to alcohol compared with nonexposed controls. The threshold dose was evaluated with the 3 prenatal alcohol exposure groups. One-way ANOVA revealed a significant between group difference for Externalizing (Aggressive and Delinquent) and the Total Problem Score. (ABSTRACT TRUNCATED)

African Americans with genotype 1 treated with interferon for chronic hepatitis C have a lower end of treatment response than Caucasians.

African Americans as a group have a higher incidence of chronic hepatitis C (CHC) than Caucasians but are often under-represented in clinical trials used to define response rates to interferon therapy. The aim of this study was to compare African Americans with Caucasians with respect to end-of-treatment response to interferon. This retrospective study had 61 African Americans and 49 Caucasians with CHC. All patients were treated for at least 12 weeks with interferon-alpha2b (Intron A) thrice weekly. End-of-treatment response was defined as three consecutive nondetectable HCV RNA measurements at least 1 month apart. Sustained response was defined as a negative serum HCV RNA 6 months after end of treatment. Of the 110 patients, 19 achieved an end-of-treatment response (17%) but only four achieved a sustained response (4/110=4%). Of the patients achieving a sustained response, one was genotype 1 (male Caucasian), three were genotype 2/3 with four patients having no follow-up information. The end-of-treatment response was 7% for patients with genotype 1 and 71% for genotype non-1 (P < 0.005 for genotype non-1). The end-of-treatment response was significantly higher in Caucasians (14/49=31%) compared with African Americans (5/61=8%; P < 0.05). A lower response rate in African Americans with genotype 1 in contrast to Caucasians was the primary reason for the difference in end-of-treatment response (1/45=2% vs. 5/33=15%, P < 0.05). Hence, interferon treatment resulted in a poor sustained response rate in the group of patients representative of the urban populations with the highest prevalence of hepatitis C. A genotype other than type 1 was the strongest predictor of end-of-treatment response in patients treated but over 86% of patients in this urban clinic were genotype 1. Caucasians were more likely to respond than African Americans, especially in patients with genotype 1.

Postnatal maturation of human GABAA receptors measured with positron emission tomography.

During brain development in nonhuman primates, there are large changes in GABAA receptor binding and subunit expression. An understanding of human GABAA receptor ontogeny is highly relevant in elucidating the pathophysiology of neurodevelopmental disorders in which GABAergic mechanisms play a role as well as in understanding differences that occur during development in the pharmacology of drugs acting on this system. We have measured age-related changes in the brain distribution of the GABAA receptor complex in vivo using positron emission tomography (PET) in epileptic children under evaluation for surgical treatment. PET imaging was performed using the tracer [11C]flumazenil (FMZ), a ligand that binds to alpha subunits of the GABAA receptor. FMZ binding was quantified using a two-compartment model yielding values for the volume of distribution (VD) of the tracer in tissue. All brain regions studied showed the highest value for FMZ VD at the youngest age measured (2 years), and the values then decreased exponentially with age. Medial temporal lobe structures, primary visual cortex, and thalamus showed larger differences between values for age 2 years and adults (approximately 50% decrease) than did basal ganglia, cerebellum, and other cortical regions (25-40% decreases). Furthermore, subcortical regions reached adult values earlier (14-17.5 years) than did cortical regions (18-22 years). The ontogeny data of FMZ VD from children may contribute to understanding regional differences in synaptic plasticity as well as improve rational therapeutic use of drugs acting at the GABAA receptor in the pediatric population.

Serial changes in levels of IL-6 and IL-1beta in premature infants at risk for bronchopulmonary dysplasia.

The aim of this study was to define the inflammatory changes occurring in the lungs of infants at risk for bronchopulmonary dysplasia (BPD) over the first 28 days of life, and to define an optimal strategy for steroids therapy in the prevention of BPD. We measured levels of interleukin-6 (IL-6) and interleukin-1 beta (IL-1beta) in tracheal aspirate (TA) samples and blood of premature infants with severe respiratory distress syndrome RDS (n = 45) on the first day of life prior to initiation of surfactant therapy and on days 5-7, 12-14, 19-21, and 26-28. Levels of IL-6 and IL-1beta were determined with a commercially available enzyme-linked immunoassay. Logistic regression analyses were performed in order to examine differences in trends in levels of IL-6 and IL-1beta between groups of infants. Infants were divided into group I (n = 30, FiO(2) < or = 0.35 at 28 days) and group II (n = 15, FiO(2) > 0.35 based on their likelihood of developing BPD at 36 weeks postconceptional age (PCA). The infants were comparable with respect to mean ( +/- SEM) birth weight (895 +/- 33 g vs. 900 +/- 40 g), gestational age (27 +/- 0.38 weeks vs. 27 +/- 0.54 weeks), and severity of respiratory illness at entry into the study (mean airway pressure: 12 +/- 1 cmH(2)O vs. 12 +/- 1 cmH(2)O, and oxygen index: 15 +/- 2 vs. 19 +/- 4) (group I vs. group II, respectively). Logistic regression analyses failed to reveal any significant differences in linear trends of levels of IL-6 and IL-1beta in TA samples between both groups of infants. No particular pattern of change in levels of IL-6 or IL-1beta could be identified among groups of infants. Levels of IL-6 and IL-1beta in TA samples on the first day of life failed to predict the need for FiO(2) > 0.35 at 28 days of age. We could not identify an increasing trend or a specific pattern of changes in postnatal levels of IL-6 or IL-1beta in TA samples of infants who were at greater risk of developing BPD at 36 weeks PCA compared to infants who were not.

Surfactant phospholipids and surface activity among preterm infants with respiratory distress syndrome who develop bronchopulmonary dysplasia.

Our objective was to determine if preterm infants with respiratory distress syndrome who develop bronchopulmonary dysplasia have abnormalities in surfactant phospholipids and/or function. Tracheal aspirate samples obtained from preterm infants with respiratory distress syndrome on days 1, 3-5, 7-10, 14-17, 21-24 and 27-30 were analyzed for total phospholipids and phospholipids fractions by determination of total phospholipid phosphorus and thin layer chromatography, respectively. Surfactant properties were assessed with captive bubble surfactometer. Sixteen out of 56 (29%) infants died during the first 30 d of life. Infants who died were more immature, required more ventilatory support and had a surfactant with lower surface-tension-reducing properties than infants who survived (p < 0.05). Surviving infants were divided into group I (no bronchopulmonary dysplasia at 27-30 d, n = 25) and group II (with bronchopulmonary dysplasia at 27-30 d, n = 15). No significant differences in concentrations of surfactant phospholipids nor measurements of surface tension were noted among groups of infants. Surfactant therapy after birth was associated with a significant increase in concentrations of total phospholipids, lecithin, phosphatidylinositol and lower surface-tension measurements at 3-5 d of age among surviving infants (p < 0.01). Abnormalities in concentrations of surfactant phospholipids or surfactant function could not be demonstrated during the first month of life among preterm infants with respiratory distress syndrome who develop bronchopulmonary dysplasia.

Nonlinear components of age-related change in sleep initiation.

BACKGROUND: Although primary studies suggest that ability to initiate sleep declines as people age, no systematic literature review has addressed the age(s) at which adults experience the greatest change in their ability to initiate sleep. OBJECTIVE: To explore whether there are any points in time across the adult life span when the rate of change in ability to initiate sleep increases or decreases. METHODS: Mathematical modeling was used to generate data points from information about central tendency, variance, and correlations between age and time to sleep onset provided by seven research reports. The reports represent 258 subjects ages 17 to 91 years. Smoothing splines were used to identify inflection points suggestive of major changes in sleep initiation across the life span. RESULTS: Two mathematical models were generated. One model suggested that inflection points may exist around ages 30 and 50 years, respectively. With this model, the amount of time until sleep onset increased until the age of 30 years, but was unchanged from ages 30 to 50 years. Ability to initiate sleep appeared to decline steadily after the age of 50 years. The second model, with a p value of 0.05, lacked adequate power to identify a significant nonlinear trend. CONCLUSIONS: Decline in ability to initiate sleep may not occur at a steady rate over the adult life span. Further research is needed to pinpoint thresholds of change and possible gender differences in thresholds.

Myocardial blood flow, function, and metabolism in repetitive stunning.

UNLABELLED: Myocardial hibernation refers to a state of persistent left ventricular dysfunction resulting from a chronically reduced blood flow, which is improved or reversed with revascularization. Increased glucose uptake in areas with reduced blood flow at rest on PET has been used successfully to diagnose hibernating myocardium. However, hibernation may represent persistent myocardial stunning resulting from repeated episodes of ischemia and reperfusion rather than from chronic underperfusion. We sought to determine the inter-relationship between blood flow, metabolism, and function in a canine model of repetitive myocardial stunning. METHODS: Ten dogs underwent 4 sequential 5-min intervals of balloon occlusion of the anterior descending or circumflex arteries, each separated by 5 min of reperfusion. Regional blood flow, metabolism, and function were evaluated 3-4 h after reperfusion in all dogs and 24 h and 1 wk after reperfusion in 5 dogs. Regional wall motion was evaluated with echocardiography. Regional blood flow was assessed with radioactive microspheres and by [(13)N]ammonia and PET. Measurements of oxidative metabolism and glucose uptake (during hyperinsulinemic-euglycemic clamping) were derived with [(11)C]-acetate, FDG, and PET. RESULTS: Regional wall motion was severely decreased after the 4 cycles of ischemia, remained impaired 24 h after reperfusion, and normalized after 1 wk. During reflow, blood flow in stunned regions was restored to near-normal levels (0.89 +/- 0.07 versus 0.95 +/- 0.07 mL/g/min, P = 0.023). However, glucose uptake in stunned regions was significantly decreased at 4 h (73% +/- 5% of remote, P < 0.001), remained depressed after 24 h of reflow (83% +/- 4% of remote, P = 0.013), and fully recovered at 1 wk (101% +/- 10% of remote, P = 0.88). Similarly, oxidative metabolism in stunned regions was significantly decreased at 4 h (84% +/- 2% of remote, P < 0.001) and at 24 h (90% +/- 2% of remote, P = 0.005) and recovered to near-normal levels after 1 wk of reperfusion (97% +/- 1% of remote, P = 0.024). The time course of change in postischemic dysfunction correlated with the recovery of oxidative metabolism (r=0.57; P=0.009). CONCLUSION: Myocardium subjected to repetitive stunning showed a prolonged yet reversible reduction in systolic function that was associated with a significant downregulation of glucose and oxidative metabolism despite restoration of normal myocardial blood flow. These findings suggest a unique metabolic adaptation in repetitive stunning that is different from that typically seen in clinical and experimental models of hibernation.

Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex.

OBJECTIVE: Using interictal alpha-[11C]methyl-l-tryptophan ([11C]AMT) PET scan, the authors have undertaken a quantitative analysis of all tubers visible on MRI or 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET, to determine the relationship between [11C]AMT uptake and epileptic activity on EEG. BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, often associated with cortical tubers and intractable epilepsy. The authors have shown previously that [11C]AMT PET scans show high tracer uptake in some epileptogenic tubers and low uptake in the remaining tubers. METHODS: Eighteen children, age 7 months to 16 years, were studied. Patients underwent video-EEG monitoring, PET scans of [11C]AMT and [18F]FDG, and T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI. [11C]AMT uptake values were measured in 258 cortical tubers delineated with coregistered MRI or [18F]FDG scans. Uptake ratios were calculated between the [11C]AMT uptake in tubers and those for normal cortex (tuber/normal cortex). Using the region of epileptiform activity, the authors performed receiver operator characteristics (ROC) analysis and determined the optimal uptake ratio for detecting presumed epileptogenic tubers. RESULTS: Tuber uptake ratios ranged from 0.6 to 2.0. Tuber uptake ratios in the epileptic lobes were higher than those in the nonepileptic lobes (p < 0.0001). All 15 patients with focal seizure activity showed one or more lesions with uptake ratio above 0.98 in the epileptic lobe. ROC analysis showed that a tuber uptake ratio of 0.98 resulted in a specificity of 0.91. CONCLUSIONS: Cortical tubers with [11C]AMT uptake greater than or equal to normal cortex are significantly related to epileptiform activity in that lobe. Together, interictal [11C]AMT PET and FLAIR MRI improve the detection of potentially epileptogenic tubers in patients with TSC being evaluated for epilepsy surgery.

Age-related changes in initiation and maintenance of sleep: a meta-analysis.

The purpose of this meta-analysis was to determine the magnitude of change over the adult life span in four key sleep characteristics and to explore research design features that may account for variability in reported age-related sleep change. Forty-one published studies (combined N = 3293) provided 99 correlational effect sizes. Waking frequency and duration increased with age as previously concluded by narrative reviewers. Although narrative reviewers were less certain whether nighttime sleep amount or the ability to initiate sleep decreased with age, the meta-analysis suggested that both decreased. When sleep variables were measured by polysomnography rather than self-report, larger age-related changes were found. Few researchers who studied normal sleep controlled for important health moderators or studied women.

A mathematical model for the analysis of cross-sectional brain glucose metabolism data in children.

1. The authors present here a 5-parameter developmental function designed to describe quantitatively the time-course of changes in glucose metabolism with age. This function consists of a plateau phase which is described by the rate of increase with age and the height of the plateau, followed by a decline phase characterized by the rate of decrease to adult levels. These two phases are separated by a distinct point in time, at which the transition between the two phases occurs. 2. The model is designed to fit published data showing that glucose metabolic rate in frontal cortex at birth is about 60% of adult values (mean adult value is 24 mumol/100 g/min) and increases to slightly less than triple adult value by age 3. The metabolic rate remains at this level until the age of approximately 8 years when it starts the decline to adult values. 3. A procedure is presented which allows the approximate computation of the 98% confidence contours in data space for the developmental function. The computation is based on the joint probability function obtained from the model covariance matrix. 4. The newly designed 5-parameter developmental function is well suited to describe maturational changes of glucose metabolism. Due to its excellent model identifiability and the interpretability of individual parameters, this function is better suited for description of maturational changes than the gamma-function. Furthermore, this function may provide a useful framework for interpretation of other data sets during development.

Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children.

Serotonin content, serotonin uptake sites, and serotonin receptor binding measured in animal studies are all higher in the developing brain, compared with adult values, and decline before puberty. Furthermore, a disruption of synaptic connectivity in sensory cortical regions can result from experimental increase or decrease of brain serotonin before puberty. The purpose of the present study was to determine whether brain serotonin synthesis capacity is higher in children than in adults and whether there are differences in serotonin synthesis capacity between autistic and nonautistic children. Serotonin synthesis capacity was measured in autistic and nonautistic children at different ages, using alpha[11C]methyl-L-tryptophan and positron emission tomography. Global brain values for serotonin synthesis capacity (K complex) were obtained for autistic children (n = 30), their nonautistic siblings (n = 8), and epileptic children without autism (n = 16). K-complex values were plotted according to age and fitted to linear and five-parameter functions, to determine developmental changes and differences in serotonin synthesis between groups. For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children.

Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia.

OBJECTIVE: To determine if an intrauterine sub-clinical inflammatory process is a risk factor for the development of bronchopulmonary dysplasia. METHODS: A cohort study was conducted in patients who met the following criteria: (1) Singleton gestation; (2) preterm labor or preterm premature rupture of the membranes; (3) amniocentesis for microbiologic studies of the amniotic fluid and (4) delivery between 24 and 28 weeks of gestation. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen for 28 days or longer after birth, associated with compatible chest radiographic findings. Amniotic fluid interleukin-8, was measured using a specific immunoassay. Logistic regression analysis and bootstrap procedure were used for statistical purposes. RESULTS: Forty-seven patients met the inclusion criteria for this study. Among these patients, the prevalence of bronchopulmonary dysplasia was 23.4% (11/47). Amniotic fluid culture was positive in 21 out of 47 (44.7%) patients. Median (range) amniotic fluid interleukin-8 concentration was higher in patients whose neonates subsequently developed bronchopulmonary dysplasia than in those who did not (17 [9.8-583.7] ng ml(-1) versus 9.6 [0.91-744] ng ml(-1), P=0.057). An amniotic fluid IL-8 level greater than 11.5 ng ml(-1) was far more common in mothers whose fetuses went on to develop bronchopulmonary dysplasia than in those who did not (10/11 [90.9%] versus 17/36 [47%]; P=0.01). This relationship remained significant even after correcting for the effect of gestational age and birthweight (Odds ratio: 11.9; P<0.05). CONCLUSION: Sub-clinical intrauterine inflammation is a risk factor for the subsequent development of bronchopulmonary dysplasia. We propose that in utero aspiration of fluid with high concentration of pro-inflammatory mediators may contribute to the lung injury responsible for the development of bronchopulmonary dysplasia.