Genome-wide association study of shared components of reading disability and language impairment.

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.

Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex.

Noncoplanar polychlorinated biphenyls (PCBs) are widely dispersed in human environment and tissues. Here, an exemplar noncoplanar PCB was fed to rat dams during gestation and throughout three subsequent nursing weeks. Although the hearing sensitivity and brainstem auditory responses of pups were normal, exposure resulted in the abnormal development of the primary auditory cortex (A1). A1 was irregularly shaped and marked by internal nonresponsive zones, its topographic organization was grossly abnormal or reversed in about half of the exposed pups, the balance of neuronal inhibition to excitation for A1 neurons was disturbed, and the critical period plasticity that underlies normal postnatal auditory system development was significantly altered. These findings demonstrate that developmental exposure to this class of environmental contaminant alters cortical development. It is proposed that exposure to noncoplanar PCBs may contribute to common developmental disorders, especially in populations with heritable imbalances in neurotransmitter systems that regulate the ratio of inhibition and excitation in the brain. We conclude that the health implications associated with exposure to noncoplanar PCBs in human populations merit a more careful examination.

Mortality of patients with childhood onset (0-17 years) Type I diabetes in Israel: a population-based study.

AIMS/HYPOTHESIS: The aim of this study was to examine the mortality rate of subjects with childhood-onset Type I (insulin-dependent) diabetes mellitus in Israel. METHODS: The whole-country cohort of 1,861 children and adolescents (0-17 years) with Type I diabetes, diagnosed between January 1965 and December 1993 in Israel, was analysed for mortality up to October 1996. RESULTS: A total of 37 deaths were identified with an ascertainment rate of 100%. There was a significant (p < 0.001) excess mortality in the patients with Type I diabetes, the standard mortality ratio being three times higher than that of the general population. The causes of mortality were ketoacidosis (n = 8), infections (n = 8), chronic diabetes complications (n = 9), external causes (n = 6) and other (n = 6). Among the subjects who died, the prevalence of nephropathy, neuropathy and anaemia was higher in female than in male subjects. A total of 17 of the patients with diabetes who died had a central nervous disease (psychosis, mental retardation, epilepsy). There was a trend to lower mortality among the Arab cohort which did not reach statistical significance. CONCLUSIONS/INTERPRETATION: Our data provide additional evidence that childhood-onset Type I diabetes carries an increased mortality risk when compared with the mortality risk of the non-diabetic population.

Seasonality of birth in children (0-14 years) with type 1 diabetes mellitus in Slovenia.

The aim of this study was to find out whether there is seasonality of month of birth of children with diabetes in Slovenia and if so whether it differs from that of the general population. A cohort of 849 children and adolescents (0-14 years) with type 1 diabetes mellitus born between 1956 and 1998 were included in the study. Monthly and seasonal patterns of birth of the patients with diabetes were compared with the pattern of normal live births (n = 1,345,921) and the pattern of disease onset. Statistical analysis was made using Student's t-test to compare the means between the four seasons of the year, and single cosinor analysis for a period of 12 months. The children and adolescents with diabetes had a statistically significant different seasonality of month of birth compared to that of the general population, and an opposite pattern from the seasonality of month of onset of disease. The observations made are in accordance with observations made recently in other countries and support the hypothesis that a virus infection transmitted by the mother to the fetus during the annual viral epidemic induces the autoimmune process in the pancreatic beta-cells in genetically susceptible individuals who will subsequently develop clinical diabetes during childhood.

Linking spontaneous activity of single cortical neurons and the underlying functional architecture.

The relation between the activity of a single neocortical neuron and the dynamics of the network in which it is embedded was explored by single-unit recordings and real-time optical imaging. The firing rate of a spontaneously active single neuron strongly depends on the instantaneous spatial pattern of ongoing population activity in a large cortical area. Very similar spatial patterns of population activity were observed both when the neuron fired spontaneously and when it was driven by its optimal stimulus. The evoked patterns could be used to reconstruct the spontaneous activity of single neurons.

Imaging cortical dynamics at high spatial and temporal resolution with novel blue voltage-sensitive dyes.

Conventional imaging techniques have provided high-resolution imaging either in the spatial domain or in the temporal domain. Optical imaging utilizing voltage-sensitive dyes has long had the unrealized potential to achieve high resolution in both domains simultaneously, providing subcolumnar spatial detail with millisecond precision. Here, we present a series of developments in voltage-sensitive dyes and instrumentation that make functional imaging of cortical dynamics practical, in both anesthetized and awake behaving preparations, greatly facilitating exploration of the cortex. We illustrate this advance by analyzing the millisecond-by-millisecond emergence of orientation maps in cat visual cortex.