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Papers of the Week

  • 1) Eur J Hum Genet. 2012 Feb 15. doi: 10.1038/ejhg.2012.24. [Epub ahead of print]

    One thing leads to another: the cascade of obligations when researchers report genetic research results to study participants.

    Miller FA, Hayeems RZ, Li L, Bytautas JP.

1] Institute of Health Policy, Management and Evaluation, University of Toronto, 
Toronto, Ontario, Canada [2] Joint Centre for Bioethics, University of Toronto,
Toronto, Ontario, Canada.

Even as debate continues about the putative obligation to proactively report
genetic research results to study participants, there is an increasing need to
attend to the obligations that might cascade from any initial report. We
conducted an international, quasi-experimental survey of researchers involved in 
autism spectrum disorders (ASD) and cystic fibrosis (CF) genetics to explore
perceived obligations to ensure updated information or relevant clinical care
subsequent to any initial communication of research results, and factors
influencing these attitudes. 5-point Likert scales of dis/agreement were analyzed
using descriptive and multivariate statistics. Of the 343 respondents (44%
response rate), large majorities agreed that in general and in a variety of
hypothetical research contexts, research teams that report results should ensure 
that participants gain subsequent access to updated information (74-83%) and
implicated clinical services (79-87%). At the same time, researchers perceived
barriers restricting access to relevant clinical care, though this was
significantly more pronounced (P<0.001) for ASD (64%) than CF (34%). In the
multivariate model, endorsement of cascading obligations was positively
associated with researcher characteristics (eg, clinical role/training) and
attitudes (eg, perceived initial reporting obligation), and negatively associated
with the initial report of less scientifically robust hypothetical results, but
unaffected by perceived or hypothetical barriers to care. These results suggest
that researchers strongly endorse information and care-based obligations that
cascade from the initial report of research results to study participants. In
addition, they raise challenging questions about how any cascading obligations
are to be met, especially where access challenges are already prevalent.European 
Journal of Human Genetics advance online publication, 15 February 2012;
doi:10.1038/ejhg.2012.24.

PMID: 22333903  [PubMed - as supplied by publisher]
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  • 2) J Autism Dev Disord. 2012 Feb 10; [Epub ahead of print]

    Patterns of Autobiographical Memory in Adults with Autism Spectrum Disorder.

    Crane L, Pring L, Jukes K, Goddard L.

Department of Psychology, Goldsmiths, University of London, New Cross, London,
SE14 6NW, UK, L.Crane@gold.ac.uk.

Two studies are presented that explored the effects of experimental
manipulations on the quality and accessibility of autobiographical memories in
adults with autism spectrum disorder (ASD), relative to a typical comparison
group matched for age, gender and IQ. Both studies found that the adults with
ASD generated fewer specific memories than the comparison group, and took
significantly longer to do so. Despite this, experimental manipulations affected
two indices of autobiographical memory (specificity and retrieval latency)
similarly in both groups. These results suggest that adults with ASD experience
a quantitative reduction in the speed and specificity of autobiographical memory
retrieval, but that when they do retrieve these memories, they do so in a way
that is qualitatively similar to that of typical adults.

PMID: 22322581 [PubMed - as supplied by publisher]
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  • 3) Eur J Neurosci. 2012 Feb 9; [Epub ahead of print]

    Language performance and auditory evoked fields in 2- to 5-year-old children.

    Yoshimura Y, Kikuchi M, Shitamichi K, Ueno S, Remijn GB, Haruta Y, Oi M, Munesue
T, Tsubokawa T, Higashida H, Minabe Y.

Department of Psychiatry and Neurobiology, Graduate School of Medical Science,
Kanazawa University, Kanazawa, Japan             Higher Brain Functions & Autism
Research, Department of Child Development, United Graduate School of Child
Development, Osaka University, Kanazawa University and Hamamatsu University
School of Medicine, Osaka University, Osaka, Japan             Research Center
for Child Mental Development, Kanazawa University, 13-1 Takara-Machi, Kanazawa,
Ishikawa 920-8641, Japan             International Education Center, Kyushu
University, Fukuoka, Japan             Department of MEG, Yokogawa Electric
Corporation, Tokyo, Japan             Department of Anesthesiology, Graduate
School of Medical Science, Kanazawa University, Kanazawa, Japan.

Language development progresses at a dramatic rate in preschool children. As
rapid temporal processing of speech signals is important in daily colloquial
environments, we performed magnetoencephalography (MEG) to investigate the
linkage between speech-evoked responses during rapid-rate stimulus presentation
(interstimulus interval < 1 s) and language performance in 2- to 5-year-old
children (n = 59). Our results indicated that syllables with this short stimulus
interval evoked detectable P50m, but not N100m, in most participants, indicating
a marked influence of longer neuronal refractory period for stimulation. The
results of equivalent dipole estimation showed that the intensity of the P50m
component in the left hemisphere was positively correlated with language
performance (conceptual inference ability). The observed positive correlations
were suggested to reflect the maturation of synaptic organisation or axonal
maturation and myelination underlying the acquisition of linguistic abilities.
The present study is among the first to use MEG to study brain maturation
pertaining to language abilities in preschool children. (c) 2012 The Authors.
European Journal of Neuroscience (c) 2012 Federation of European Neuroscience
Societies and Blackwell Publishing Ltd.

PMID: 22321133 [PubMed - as supplied by publisher]
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  • 4) Pharmacogenomics J. 2012 Feb 14. doi: 10.1038/tpj.2012.3. [Epub ahead of print]

    Gray matter textural heterogeneity as a potential in-vivo biomarker of fine structural abnormalities in Asperger syndrome.

    Radulescu E, Ganeshan B, Minati L, Beacher FD, Gray MA, Chatwin C, Young RC,
Harrison NA, Critchley HD.

1] Department of Psychiatry, Brighton & Sussex Medical School (BSMS), Brighton,
UK [2] Sackler Centre for Consciousness Science, University of Sussex, Brighton, 
UK.

Brain imaging studies contribute to the neurobiological understanding of Autism
Spectrum Conditions (ASC). Herein, we tested the prediction that distributed
neurodevelopmental abnormalities in brain development impact on the homogeneity
of brain tissue measured using texture analysis (TA; a morphological method for
surface pattern characterization). TA was applied to structural magnetic
resonance brain scans of 54 adult participants (24 with Asperger syndrome (AS)
and 30 controls). Measures of mean gray-level intensity, entropy and uniformity
were extracted from gray matter images at fine, medium and coarse textures.
Comparisons between AS and controls identified higher entropy and lower
uniformity across textures in the AS group. Data reduction of texture parameters 
revealed three orthogonal principal components. These were used as
regressors-of-interest in a voxel-based morphometry analysis that explored the
relationship between surface texture variations and regional gray matter volume. 
Across the AS but not control group, measures of entropy and uniformity were
related to the volume of the caudate nuclei, whereas mean gray-level was related 
to the size of the cerebellar vermis. Similar to neuropathological studies, our
study provides evidence for distributed abnormalities in the structural integrity
of gray matter in adults with ASC, in particular within corticostriatal and
corticocerebellar networks. Additionally, this in-vivo technique may be more
sensitive to fine microstructural organization than other more traditional
magnetic resonance approaches and serves as a future testable biomarker in AS and
other neurodevelopmental disorders.The Pharmacogenomics Journal advance online
publication, 14 February 2012; doi:10.1038/tpj.2012.3.

PMID: 22333911  [PubMed - as supplied by publisher]
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  • 5) Neuroimage. 2012 Feb 3; [Epub ahead of print]

    Characteristic cortical thickness patterns in adolescents with autism spectrum disorders: Interactions with age and intellectual ability revealed by canonical correlation analysis.

    Misaki M, Wallace GL, Dankner N, Martin A, Bandettini PA.

To investigate patterns and correlates of cortical thickness in adolescent males
with autism spectrum disorders (ASD) versus matched typically developing
controls, we applied kernel canonical correlation analysis to whole brain
cortical thickness with the explaining variables of diagnosis, age, full-scale
IQ, and their interactions. The analysis found that canonical variates (patterns
of cortical thickness) correlated with each of these variables. The diagnosis-
and age-by-diagnosis-related canonical variates showed thinner cortex for
participants with ASD, which is consistent with previous studies using a
univariate analysis. In addition, the multivariate statistics found larger
affected regions with higher sensitivity than those found using univariate
analysis. An IQ-related effect was also found with the multivariate analysis.
The effects of IQ and age-by-IQ interaction on cortical thickness differed
between the diagnostics groups. For typically developing adolescents, IQ was
positively correlated with cortical thickness in orbitofrontal, postcentral and
superior temporal regions, and greater thinning with age was seen in dorsal
frontal areas in the superior IQ (>120) group. These associations between IQ and
cortical thickness were not seen in the ASD group. Differing relationships
between IQ and cortical thickness implies independent associations between
measures of intelligence and brain structure in ASD versus typically developing
controls. We discuss these findings vis-a-vis prior results obtained utilizing
univariate methods. Copyright A(c) 2012. Published by Elsevier Inc.

PMID: 22326986 [PubMed - as supplied by publisher]
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  • 6) Biochim Biophys Acta. 2012 Feb 2; [Epub ahead of print]

    Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors.

    Wei H, Chadman KK, McCloskey DP, Sheikh AM, Malik M, Brown WT, Li X.

Department of Neurochemistry, NY State Institute for Basic Research in
Developmental Disabilities, New York, NY 10314, USA; Shanghai Mental Health
Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030,
China.

Abnormal immune responses have been reported to be associated with autism. A
number of studies showed that cytokines were increased in the blood, brain, and
cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has
been a consistent finding. However, the mechanisms by which IL-6 may be involved
in the pathogenesis of autism are not well understood. Here we show that mice
with elevated IL-6 in the brain display many autistic features, including
impaired cognitive abilities, deficits in learning, abnormal anxiety traits and
habituations, as well as decreased social interactions. IL-6 elevation caused
alterations in excitatory and inhibitory synaptic formations and disrupted the
balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also
resulted in an abnormal change in the shape, length and distributing pattern of
dendritic spines. These findings suggest that IL-6 elevation in the brain could
mediate autistic-like behaviors, possibly though the imbalances of neural
circuitry and impairments of synaptic plasticity. Copyright (c) 2012. Published
by Elsevier B.V.

PMID: 22326556 [PubMed - as supplied by publisher]
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  • 7) Eur Child Adolesc Psychiatry. 2012 Feb 10; [Epub ahead of print]

    Presence of GAD65 autoantibodies in the serum of children with autism or ADHD.

    Rout UK, Mungan NK, Dhossche DM.

Department of Surgery, University of Mississippi Medical Center, Clinical
Sciences Building, Room L020, Jackson, MS, 39216, USA, urout@umc.edu.

Antibodies against glutamic acid decarboxylase 65 (GAD65) have been detected in
the serum of patients with several neurological disorders. The presence of
antibodies against GAD65 has not yet been examined in the serum of patients with
neurodevelopmental disorders such as autism or attention-deficit/hyperactivity
disorder (ADHD). In this study, GAD65 antibodies and total IgG were assayed in
the serum of normal subjects and patients diagnosed with autism or ADHD. GAD65
antibodies were detected in the serum of 15% of children with autism (N = 20),
27% of children with ADHD (N = 15) and of none of the controls (N = 14). The
serum of 60% of autistic and 53% of ADHD patients reacted with Purkinje neurons
in mouse cerebellum. Serum from 20% of ADHD patients reacted also with the cells
in the molecular and granule cell layers and cells in the vicinity of the
Purkinje neurons. No association was found between the titer of GAD65 antibodies
and total IgG levels, and presence of seizures or mental retardation. None of
the ADHD patients were diagnosed with mental retardation. Serum anti-GAD65
antibodies may be a common marker of subgroups of patients with autism and ADHD.
Reactions of serum antibodies with the cells in the cerebellum in these patients
suggest direct effects on brain function. The subgroup of children with autism
and ADHD that tests positive for GAD65 antibodies needs further characterization
in a larger study.

PMID: 22323074 [PubMed - as supplied by publisher]
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