bluuebunny/crossref_metadata_2025 huggingface dataset:
Clumsiness and Disturbed Cerebellar Development: Insights From Animal Experiments
Authors: Gramsbergen Albert
Published: March 2007

Cerebellar functioning has been implied in
the fine adjustments of muscle tone, in the
coordination and the feed‐forward control of
movements and posture, as well as in the
establishment and performance of motor skills.
The cerebellar cortex in mammals develops late
in neuro‐ontogeny and an extrapolation from
experimental results indicates that in the
human the proliferation of the granule cells and
the development of circuitry in the cerebellar
cortex starts only in the last trimester of
pregnancy and lasts until beyond the first
birthday. This late development makes the
cerebellar development particularly vulnerable
to situations like an insufficient supply of
nutrients, which may follow placental dysfunction,
or to side effects of pharmacological
treatments like the administration of corticosteroids
in the postnatal period. We studied
whether such situations might also lead to
motor impairments. In rats, the effects of
undernutrition during the brain growth spurt
were investigated as well as those of
corticosteroids administered in a period that is
analogous to the 7th to 8th month of pregnancy
in the human. Both these interferences affect
cerebellar development and our results in rats
indicate that they also lead to retardations in
the, emergence of certain reflexes, as well as to
longer lasting motor impairments during
locomotion. Extrapolation of these results
strongly suggests that a disturbed cerebellar
development should be considered as an
important etiological factor in clumsiness in
human children.
Development of Action and the Clinical Continuum
Authors: Hopkins Brian
Published: March 2007

The development of action is depicted as
consisting of changes in the task‐specific
couplings between perception, movement, and
posture. It is argued that this approach may
provide a much needed basis from which
attempts can be made at theoretically unifying
the constituents of the clinical continuum (viz.,
early detection, diagnosis, prognosis, and
intervention). Illustrative examples germane to
this approach are given with regard to how
posture serves as a constraint on the emergence
of reaching movements and how cortical
development influences the coordination of leg
movements as revealed by a study involving
infants with white matter lesions. Particular
attention is paid to early detection and it is
recommended that further improvements to
this aspect of the clinical continuum can be
derived from combining serial qualitative and
quantitative (kinematic) assessments with
brain‐imaging techniques. It is emphasized that
quantitative assessments should incorporate
experimental manipulations of perception,
movement or posture during transitional
periods in development. Concluding comments
include consideration of the timing of early
intervention.
Changes in Body Temperature and Sleep‐Wakefulness AfterIntrapreoptic Injection of Methoxamine in Rats
Authors: Vetrivelan Ra. , Mallick Hruda Nanda , Kumar Velayudhan Mohan
Published: March 2007

Several pieces of evidence suggest that the
noradrenergic afferents in the medial preoptic
area produce sleep and hypothermia by acting
on α1
adrenergic receptors. On the other hand,
in a few studies monitoring body temperature
with a rectal probe, preoptic injection of the α1

adrenergic agonist methoxamine produced
contradictory changes in body temperature and
sleep‐wakefulness. Such contradictions call for
the re‐examination of methoxamine induced
body temperature changes using a better
technique like telemetric recording. In the
present study, we monitored body temperature
and sleep‐wakefulness simultaneously after the
micro‐injection of 0.5, 1, and 2 μmol
methoxamine, into the medial preoptic area of
adult male Wistar rats. Methoxamine injection
produced hypothermia but no major change in
sleep‐wakefulness during the 3 hours after drug
injection, except for a short period (15 min) of
sleep after 120 min of injection. A short period
of wakefulness, coinciding with the maximum
fall in body temperature (30 min after injection)
occurred when methoxamine was administered
at higher doses. The results of this study indicate
that 1 adrenergic receptors participate in preoptically
mediated thermoregulatory measures
that reduce body temperature. Hypothermia
induced by methoxamine might have masked
the hypnogenic action of this drug.
Perceptual Deficits in Clumsy Children: Inter‐ and Intra‐Modal Matching Approach—A Window into Clumsy Behavior
Authors: Sigmundsson H.
Published: March 2007

This article will focus on the underlying
perceptual deficits that might lead to
inadequacies in motor performance in children.
Two lines of enquiry have dominated the
literature: visual‐perceptual deficit and/or visualmotor
deficits and proprioceptive deficits. The
theoretical and methodological shortcomings in
these approaches are discussed. Then attention
is primarily directed toward the concept of
inter‐ and intra‐modal matching (sensory integration),
particularly with respect to vision and
proprioception, an ability deemed, to underlie
many real‐life motor skills. Such an approach
allows parallels to be drawn between behavioral
manifestations of motor impairment and
potential underlying neurological informationprocessing
disorders, particularly as these
relate to hemispheric competence.
Reinstatement of Morphine‐Induced ConditionedPlace Preference in Mice by Priming Injections
Authors: Do Couto B. Ribeiro , Aguilar M. A. , Manzanedo C. , Rodríguez-Arias M. , Miñarro J.
Published: March 2007

To construct a model of relapse of drug
abuse in mice, the induction, we evaluated the
extinction and reinstatement of morphine‐induced
place preference. In Experiment 1, we
examined the effects of morphine (0, 2, 3, 5, 10,
20 and 40 mg/kg) in the conditioned place
preference (CPP) paradigm. Mice showed CPP
with 5, 10, 20 and 40 mg/kg. In Experiment 2,
we evaluated the effects of two different extinction
procedures. After conditioning with 40
mg/kg of morphine, the mice underwent daily
extinction sessions of 60 or 15 min of duration.
CPP was extinguished after seven and nine
sessions, respectively. In Experiment 3, we
tested the reinstating effects of several priming
doses of morphine. Mice were conditioned with
40 mg/kg of morphine and underwent the daily
15 min extinction sessions until CPP was no
longer evident. Then, the effects of morphine (0,
2, 3, 5, 10, 20, 40 mg/kg, i.p.) were evaluated.
CPP was reinstated by doses from 5 mg/kg
upward. The results show that morphine priming
injections are effective in reactivating opiateseeking
behavior in mice, and thus, the CPP
paradigm might be useful to investigate the
mechanisms underlying relapse of drug abuse.
Effect of Donepezil on Group II mGlu Receptor Agonist‐ or Antagonist‐Induced Amnesia on Passive Avoidance in Mice
Authors: Sato Tomoaki , Tanaka Koh-ichi , Ohnishi Yoshiko , Irifune Masahiro , Nishikawa Takashige
Published: March 2007

We examined the effect of the acetylcholinesterase
(ACHE) inhibitor, donepezil
hydrocloride (DONP), on group II metabotropic
glutamate (mGlu) receptor agonist‐ or
antagonist‐induced amnesia in the step‐through
passive avoidance task in male mice. DCG‐IV, a
group II mGlu receptor agonist, at dose of 50
ng and LY341495, a group II mGlu receptor
antagonist, at dose of 300 ng, significantly
attenuated the latency on the step‐through task.
The subcutaneous injection of DONP at dose of
1 mg/kg 1 hour before passive avoidance
performance ameliorated the amnesia induced
by DCG‐IV and LY341495, whereas donepezil
alone did not affect task latency. The results
suggest that activation of group II mGlu
receptors and disinhibition of the cAMP/PKA
signaling pathway (caused by group II mGlu
receptor antagonist) have a negative action on
step‐through passive avoidance memory
performance, and that group II mGlu receptors
and ACh interact to modulate learning and
memory function.
Enhancement of Latent Inhibition by Chronic Mild Stress in RatsSubmitted to Emotional Response Conditioning
Authors: Melo Liana Lins , Ferrari Elenice A. de Moraes , Teixeira Nancy Airoldi , Sandner Guy
Published: March 2007

This work evaluated the influence of
chronic mild stress on latent inhibition (LI) in
rats, using a conditioned emotional response
(CER) procedure. Rats were assigned to four
groups: a non pre‐exposed control group (NPC),
a non pre‐exposed stressed group (NPS), a preexposed
control group (PC), and a pre‐exposed
stressed group (PS). Stressed animals were
submitted to a chronic mild stress (CMS)
regimen for three weeks. The off‐baseline
conditioned emotional response procedure had
four phases: licking response training, tone‐
shock conditioning, retraining, and testing.
Conditioning consisted of 2 tone (30 s) and
shock (0.5 s) associations. Tone‐shock conditioning
evidenced by NPS and NPC groups
suggests that stress did not interfere with the
expression of a conditioned emotional response.
Pre‐exposure was carried out using 6 tones
(30 s) during 2 sessions before conditioning.
Prior exposure to the tone resulted in a
decrease in learning that was greater in
stressed animals. The results indicate an
increase in latent inhibition induced by chronic
mild stress. Such LI potentiation after CMS
may be related to dopamine (DA) neurotransmission
reduction in the central nervous
system.
Principles of Force Gradation in Skeletal Muscles
Authors: Kernell D.
Published: March 2007

A brief survey is given of how motoneurons
and motor units are used for the gradation Of
muscle force during motor behavior. Basic
properties of motoneurons and muscle fibers,
including major kinds of functional specialization
along the axis of ‘fast’ vs. ‘slow’, are reviewed.
The principles underlying the rate and recruitment
gradation of force are described, stressing
that the properties of motoneurons and muscle
fibers are matched to automate important
aspects of the gradation procedure. Recent
investigations concerning synaptically evoked
changes in the discharge properties of motoneurons
receive special attention, including
‘plateau’ currents and, under appropriate
conditions, self‐sustained ‘plateau’ discharges.
The Nature of Hyperactivity in Children and Adolescents With Hydrocephalus: A Test of the Dual Pathway Model
Authors: Stevenson Jim , Cate Ineke Pit-ten
Published: March 2007

To determine the strength and nature of the association between hydrocephalus and hyperactivity
and to test the dual pathway model (DPM) of AD/HD, we compared a group of 51 children and adolescents with hydrocephalus with 57 normally developing controls from the general population on a battery of neuropsychological
assessments. The mean hyperactivity scores were significantly greater in the group with hydrocephalus (effect size =0.94). This association was not just part of a general elevated rate of behavior problems and was not
affected by sex or age. Variation in the clinical features of hydrocephalus was not related to the severity of hyperactivity. Path analysis was used to examine the relation between IQ, delay aversion, and executive function. In accordance with the DPM, the effect of hydrocephalus on hyperactivity was completely mediated via delay aversion and executive functions.
From the Search for a Molecular Code of Memory to the Role of Neurotransmitters: A Historical Perspective
Authors: Chapouthier Georges
Published: March 2007

The history of the neurochemistry of mnesic
processes can be divided into two main periods:
the first (1946‐1978) was inspired by the results
of molecular genetics, providing evidence for
storage of hereditary information in the DNA
of genes. Therefore, the chemical bases for
memory were investigated in the macromolecules
of the brain. Such attempts were
relatively unsuccessful, which led to a second
period (starting in 1978) with the research
emphasizing, in a less ambitious way, the role of
the molecular correlates of mnesic processes, in
particular in the main transmitter systems of
the brain.
Norepinephrine and Dopamine as Learning Signals
Authors: Harley Carolyn W.
Published: March 2007

The present review focuses on the hypothesis
that norepinephrine (NE) and dopamine (DA)
act as learning signals. Both NE and DA are
broadly distributed in areas concerned with the
representation of the world and with the
conjunction of sensory inputs and motor outputs.
Both are released at times of novelty and
uncertainty, providing plausible signal events
for updating representations and associations.
These catecholamines activate intracellular
machinery postulated to serve as a memory‐formation
cascade. Yet, despite the plausibility
of an NE and DA role in vertebrate learning
and memory, most evidence that they provide a
learning signal is circumstantial. The major
weakness of the data available is the lack of a
specific description of how the neural circuit
modulated by NE or DA participates in the
learning being analyzed. Identifying a conditioned
stimuli (CS) representation would facilitate the
identification of a learning signal role for NE or
DA. Describing how the CS representation
comes to relate to learned behavior, either
through sensory‐sensory associations, in which
the CS acquires the motivational significance of
reward or punishment, thus driving appropriate
behavior, or through direct sensory‐motor
associations is necessary to identify how NE and DA participate in memory creation. As
described here, evidence consistent with a
direct learning signal role for NE and DA is
seen in the changing of sensory circuits in odor
preference learning (NE), defensive conditioning
(NE), and auditory cortex remodeling in adult
rats (DA). Evidence that NE and DA contribute
to normal learning through unspecified
mechanisms is extensive, but the details of that
support role are lacking.
Genetic Dissection of Learning and Memory in Mice
Authors: Mineur Yann S. , Crusio Wim E. , Sluyter Frans
Published: March 2007

In this minireview, we discuss different strategies to dissect genetically the keystones of learning and memory. First, we broadly sketch the neurogenetic analysis of complex traits in mice. We then discuss two general strategies to find genes affecting learning and memory: candidate gene studies and whole genome searches. Next, we briefly review more recently developed techniques, such as microarrays and RNA interference. In addition, we focus on gene‐environment interactions and endophenotypes. All sections are illustrated with examples from the learning and memory field, including a table summarizing the latest information about genes that have been shown to have effects on learning and memory.
A Chronic Implant to Record Electroretinogram, Visual Evoked Potentials and Oscillatory Potentials in Awake, Freely Moving Rats for Pharmacological Studies
Authors: Guarino Irene , Loizzo Stefano , Lopez Luisa , Fadda Antonello , Loizzo Alberto
Published: March 2007

Electroretinogram (ERG), widely used to
study the pharmacological effects of drugs in
animal models (e.g., diabetic retinopathy), is
usually recorded in anesthetized rats. We report
here a novel simple method to obtain chronic
implantation of electrodes for simultaneous
recording at the retinal and cortical levels in
freely moving, unanesthetized animals. We
recorded cortical (VEPs) and retinal (ERGs)
responses evoked by light (flash) stimuli in
awake rats and compared the results in the
same rats anesthetized with urethane (0.6
mg/kg) before and after the monocular administration
of scopolamine methyl bromide (1%
solution). We also compared the retinal
responses with those derived from a classic acute
corneal electrode. Anesthesia induced consistent
changes of several VEP and ERG parameters
like an increase of both latency and amplitude.
In particular, the analysis of the variation of
latency, amplitude, and spectral content of
rapid oscillatory potentials could be important
for a functional evaluation of the visual system
in unanesthetized versus anesthetized animals.
Emerging Developmental Pathways to ADHD: Possible Path Markers in Early Infancy
Authors: Auerbach Judith G. , Atzaba-Poria Naama , Berger Andrea , Landau Rivka
Published: March 2007

Sixty‐six male infants participating in the Ben‐Gurion Infant Development Study of familial risk for attention deficit hyperactivity disorder (ADHD)were assessed at 7 months of age using observational and mother report measures. Risk for ADHD was based on ADHD symptoms in the father. Infants whose fathers had seven or more symptoms formed the ADHD risk group; infants whose fathers had three or less symptoms formed the comparison group. The ADHD risk group significantly differed from the comparison group on measures of interest, anger, and activity level and showed less interest in block play and more anger reactivity but less directed anger in a
barrier task. According to mother report, the ADHD risk group had higher levels of activity
than the comparison group. Measures of neonatal immaturity and activity were related to behavior at 7 months. The findings suggest that possible developmental pathways to ADHD may be emerging in early infancy.
Effects of Neonatal Treatment With 6‐Hydroxydopamine and Endocrine Disruptors on Motor Activity and Gene Expression in Rats
Authors: Masuo Yoshinori , Ishido Masami , Morita Masatoshi , Oka Syuichi
Published: March 2007

To investigate the mechanisms underlying
motor hyperactivity, we performed intracisternal
injection of 6‐hydroxydopamine or
endocrine disruptors in rats on postnatal day 5.
6‐Hydroxydopamine (100 μg, 488 nmol) caused
a significant increase in spontaneous motor
activities at 4 weeks of age. Gene‐expression
profiling using a cDNA membrane array
revealed alterations in several classes of gene at
8 weeks of age. In the midbrain, gene expression
was enhanced in dopamine transporter 1; a
platelet‐derived growth factor receptor;
dopamine receptor D4; galanin receptor 2;
arginine vasopressin receptor 2; neuropeptide Y;
tachykinin 2; and fibroblast growth factor 10.
Expression was also enhanced in the
glutamate/aspartate transporter gene in the
striatum. Rats received an endocrine disruptor
(87 nmol), such as bisphenol A, nonylphenol, p‐octylphenol,
or diethylhexylphthalate, which
also caused motor hyperactivity at 4 weeks.
The effects of bisphenol A on motor activity
were dose‐dependent from 0.87 to 87 nmol. The
phenols caused a deficit in dopamine neurons,
similarly to the deficit caused by 6‐hydroxydopamine.
Gene‐expression profiles after
treatment with endocrine disruptors showed
variation and differed from those of 6‐
hydroxydopamine. The results suggest that
neonatal treatment with environmental
chemicals can generate an animal model of
attention‐deficit hyperactivity disorder, in
which clinical symptoms are pervasive.
Experimental Investigations on Dopamine Transmission Can Provide Clues on the Mechanism of the Therapeutic Effect of Amphetamine and Methylphenidate in ADHD
Authors: Carboni Ezio , Silvagni Alessandra
Published: March 2007

The aim of this review is to compare the
experimental evidence obtained from in vitro
studies on the effect of amphetamine and
methylphenidate on dopamine transmission with
the results obtained in animal models of
attention deficit hyperactivity disorder (ADHD).
This comparison can extend the knowledge on
the mechanism of action of the drugs used in
the therapy of ADHD and provide insight into
the etiology of ADHD. In particular, we
considered the results obtained from in vitro
methods, such as synaptosomes, cells in culture,
and slices and from in vivo animal models of
ADHD, such as spontaneous hypertensive rats
(SHR) and the Naples high‐excitability (NHE)
rat lines. The different experimental approaches
produce consonant results and suggest that in
SHR rats, in contrast to Wistar Kyoto rats
(WKY), amphetamine and depolarization by
high K+ might release different pools of
dopamine‐containing vesicles. The pool depleted
by amphetamine might represent dopamine
that is stored in large dense core vesicles,
whereas dopamine released by high K+ might
be contained in small synaptic vesicles (SSV).
The sustained dopamine transmission observed
in the nucleus accumbens of SHR but not WKY
rats can be supported by an elevated synthesis
and release, which also might explain the
stronger effect of methylphenidate on dopamine
release in SHR but not in WKY rats. This
hypothesis might enlighten the common
therapeutic effect of these drugs, although their
action takes place at different levels in
catecholaminergic transmission.
Dysfunctions in Dopamine Systems and ADHD: Evidence From Animals and Modeling
Authors: Viggiano Davide , Vallone Daniela , Sadile Adolfo
Published: March 2007

Animal models are useful for characterizing
neural substrates of neuropsychiatric disorders.
Several models have been proposed for the
study of Attention Deficit Hyperactivity Disorder
(ADHD). The models can be divided into various
groups: (i) genetically derived hyperactivity/
inattention, (ii) animal models showing symptoms
after pharmacological intervention, and (iii)
those based on spontaneous variations in a
random population. Spontaneously hypertensive
(SHR) and Naples High Excitability (NHE) rats
show behavioral traits featuring the main
aspects of ADHD in humans but show different
changes in dopamine (DA) systems. In fact, the
enzyme tyrosine hydroxylase is hyperexpressed
in NHE rats and hypoexpressed in SHR. The DA
transporter is hyperexpressed in both lines,
although in the SHR, DAT activity is low
(reduced DA uptake). The DA levels in the
striatum and prefrontal cortex are increased in
the juvenile SHR, but are decreased in handled
young and non‐handled older animals. The
mRNA of the D1 DA receptor is upregulated
in the prefrontal cortex of SHR and downregulated
in NHE. The D2 DA receptors are
likely to be hypofunctioning in SHR, although
the experimental evidence is not univocal,
whereas their mRNA is hyperexpressed in
NHE. Thus, in SHR both the mesocortical and
mesolimbic DA pathways appear to be
involved, whereas in NHE only the mesocortical
system. To understand the effects of
methylphenidate, the elective ADHD drug
treatment in humans, in a dysfunctioning DA
system, we realized a simple mathematical
model of DA regulation based on experimental
data from electrophysiological, cyclic
voltammetry, and microdialysis studies. This
model allows the estimation of a higher firing
frequency of DA neurons in SHR rats and
suggests that methylphenidate increases
attentive processes by regulating the firing rate
of DA neurons.
Postural Synergies and Their Development
Authors: Latash Mark L. , Krishnamoorthy Vijaya , Scholz John P. , Zatsiorsky Vladimir M.
Published: March 2007

The recent developments of a particular approach to analyzing motor synergies based on the principle of motor abundance has allowed a quantitative assessment of multieffector coordination in motor tasks involving anticipatory adjustments to self‐triggered postural perturbations and in voluntary posturalsway. This approach, the uncontrolled manifold (UCM) hypothesis, is based on an assumption that the central nervous system organizes covariation of elemental variables to stabilize important performance variables in a task‐specific manner. In particular, this approach has been used to demonstrate and to assess the emergence of synergies and their modification with motor practice in typical persons and persons with Down syndrome. The framework of the UCM hypothesis allows the formulation of testable hypotheses with respect to developing postural synergies in typically and atypically developing persons.
Development of Postural Muscles and Their Innervation
Authors: IJkema-Paassen J. , Gramsbergen A.
Published: March 2007

Control of posture is a prerequisite for efficient motor performance. Posture depends on muscles capable of enduring contractions, whereas movements often require quick, forceful muscle actions. To serve these different goals, muscles contain fibers that meet these different tasks. Muscles with strong postural functions mainly consist of slow muscle fibers with a great resistance against fatigue. Flexor muscles in the leg and arm muscles are mainly composed of fast muscle fibers producing relatively large forces that are rapidly fatigable. Development of the neuromuscular system continues after birth. We discuss in the human baby and in animal experiments changes in muscle fiber properties, regression from polyneural into mononeural innervation, and developmental changes in the motoneurons of postural muscles during that period. The regression of poly‐neural innervation in postural muscles and the development of dendrite bundles of their motoneurons seem to be linked to the transition from the immature into the adult‐like patterns of moving and postural control.
Cerebellar Development and Plasticity: Perspectives for Motor Coordination Strategies, for Motor Skills, and for Therapy
Authors: Swinny J. D. , van der Want J. J. L. , Gramsbergen A.
Published: March 2007

The role of the mammalian cerebellum ranges from motor coordination, sensory‐motor integration, motor learning, and timing to nonmotor functions such as cognition. In terms of motor function, the development of the cerebellum is of particular interest because animal studies show that the development of the cerebellar cortical circuitry closely parallels motor coordination. Ultrastructural analysis of the morphological development of the cerebellar circuitry, coupled with the temporal and spatial identification of the neurochemical substrates expressed during development, will help to elucidate their roles in the establishment of the cerebellar circuitry and hence motor activity. Furthermore, the convenience of a number of naturally occurring mouse mutations has allowed a functional dissection of the various cellular elements that make up the cerebellar circuitry. This understanding will also help in the approach to possible therapies of pathologies arising during development because tile cerebellum is especially prone to such perturbation because of its late development.
Postural Behavior in Children Born Preterm
Authors: Fallang Bjørg , Hadders-Algra Mijna
Published: March 2007

The present paper presents clinical and neurophysiological data of postural behavior in preterm children without CP. Clinical followup studies of preterm infants until toddler and school age have reported that low‐risk preterm infants may have atypical postural behavior in terms of reduced amount of rotation during crawling, delayed dynamic balance, delayed onset of and a poor quality of early walking behavior. At school age, dysfunctions such as problems in standing on one leg and poor hopping are reported. Neurophysiological data of postural control at early age indicated the presence of a dysfunction in the capacity to modulate postural activity, and the postural activity has been characterized by temporal disorganization of EMG responses. Postural responses to goal‐directed reaching in supine lying have been recorded and analyzed in terms of the total body center of pressure. In this study, preterm infants show less mobile postural behavior compared with full‐term infants. In infancy, the less mobile postural behavior seemed to be adequate as it was related to better goal‐directed reaching quality, but the results indicated that the relatively immobile postural behavior during reaching in early age was related to less favorable neuromotor behavior in school‐age.
Postural Control in Children With Developmental Coordination Disorder
Authors: Geuze Reint H.
Published: March 2007

The development of static balance is a basic characteristic of normal motor development. Most developmental motor tests include a measure of static balance. Children with Developmental Coordination Disorder (DCD) often fail this item. This study reviews the balance problems of children with DCD. The general conclusion is drawn that under normal conditions static balance control is not a problem for children with DCD. Only in difficult, unattended, or novel situations such children seem to suffer from increased postural sway. These findings raise the question of what happens when balance is lost. The present study addresses the strength of correlation between the electromyography (EMG) and force plate signals in one‐leg stance over epochs of stable and unstable balance. Four groups of children were involved in the study: two age groups and a group of children with DCD and balance problems and their controls. The results show a clear involvement of tibialis anterior and peroneus muscles in the control of lateral balance in all conditions and groups. The group of children with DCD and balance problems,however, showed a weaker coupling between EMG and corrective force compared with control children, indicating non‐optimal balance control. An evaluation of the existing data in terms of evidence of specific structural deficits associated with DCD provided converging evidence that suggests cerebellar involvement.
Postural Dysfunction During Standing and Walking in Children With Cerebral Palsy: What are the Underlying Problems and What New Therapies Might Improve Balance?
Authors: Woollacott Marjorie Hines , Shumway-Cook Anne
Published: March 2007

In this review we explore studies related to constraints on balance and walking in children with cerebral palsy (CP) and the efficacy of training reactive balance (recovering from a slip induced by a platform displacement) in children with both spastic hemiplegic and diplegic CP. Children with CP show (a) crouched posture, contributing to decreased ability to recover balance (longer time/increased sway); (b) delayed responses in ankle muscles; (c) inappropriate muscle response sequencing; (d) increased coactivation of agonists/antagonists. Constraints on gait include (a) crouched gait; (b) increased co‐activation of agonists/antagonists; (c) decreased muscle activation; (d) spasticity. The efficiency of balance recovery can be improved in children with CP, indicated by both a reduction in the total center of pressure path used during balance recovery and in the time to restabilize balance after training. Changes in muscle response characteristics contributing to improved recovery include reductions in time of contraction onset, improved muscle response organization, and reduced co‐contraction of agonists/antagonists. Clinical implications include the suggestion that improvement in the ability to recover balance is possible in school age children with CP.
A Critical Review of Constraint‐Induced Movement Therapy and Forced Use in Children With Hemiplegia
Authors: Charles Jeanne , Gordon Andrew M.
Published: March 2007

Hemiplegia is a physical impairment that can occur in childhood following head trauma, cerebral vascular accident or transient ischemic attack (stroke), brain tumor, or congenital or perinatal injury. One of the most disabling symptoms of hemiplegia is unilaterally impaired hand and arm function. Sensory and motor impairments in children with hemiplegia compromise movement efficiency. Such children often tend not to use the affected extremity, which may further exacerbate the impairments, resulting in a developmentally learned non‐use of the involved upper extremity, termed ‘developmental disuse’. Recent studies suggest that children with hemiplegia benefit from intensive practice. Forced use and Constraint‐lnduced Movement Therapy (CI therapy) are recent therapeutic interventions involving the restraint of the non‐involved upper extremity and intensive practice with the involved upper extremity. These approaches were designed for adults with hemiplegia, and increasing evidence suggests that they are efficacious in this population. Recently, forced use and constraint‐induced therapy have been applied to children with hemiplegia. In this review, we provide a brief description of forced use and CI therapy and their historical basis, provide a summary of studies of these interventions in children, and discuss a number of important theoretical considerations, as well as implications for postural control. We will show that whereas the studies to date suggest that both forced use and CI therapy appear to be promising for improving hand function in children with hemiplegia, the data are limited. Substantially more work must be performed before this approach can be advocated for general clinical use.
Memory Effects of Benzodiazepines: Memory Stages and Types Versus Binding‐Site Subtypes
Authors: Savić Miroslav M. , Obradović Dragan I. , Ugrešić Nenad D. , Bokonjić Dubravko R.
Published: March 2007

Benzodiazepines are well established as inhibitory modulators of memory processing. This effect is especially prominent when applied before the acquisition phase of a memory task. This minireview concentrates on the putative subtype selectivity of the acquisition‐impairing action of benzodiazepines. Namely, recent genetic studies and standard behavioral tests employing subtype‐selective ligands pointed to the predominant involvement of two subtypes of benzodiazepine binding sites in memory modulation. Explicit memory learning seems to be affected through the GABAA receptors containing the α1 and α5 subunits, whereas the effects on procedural memory can be mainly mediated by the α1 subunit. The pervading involvement of the α1 subunit in memory modulation is not at all unexpected because this subunit is the major subtype, present in 60% of all GABAA receptors. On the other hand, the role of α5 subunits, mainly expressed in the hippocampus, in modulating distinct forms of memory gives promise of selective pharmacological coping with certain memory deficit states.
The Role of Insulin, Insulin Growth Factor, and Insulin‐Degrading Enzyme in Brain Aging and Alzheimer′s Disease
Authors: Messier Claude , Teutenberg Kevin
Published: March 2007

Most brain insulin comes from the pancreas and is taken up by the brain by what appears to be a receptor‐based carrier. Type 2 diabetes animal models associated with insulin resistance show reduced insulin brain uptake and content. Recent data point to changes in the insulin receptor cascade in obesity‐related insulin resistance, suggesting that brain insulin receptors also become less sensitive to insulin, which could reduce synaptic plasticity. Insulin transport to the brain is reduced in aging and in some animal models of type 2 diabetes; brain insulin resistance may be present as well. Studies examining the effect of the hyperinsulinic clamp or intranasal insulin on cognitive function have found a small but consistent improvement in memory and changes in brain neuroelectric parameters in evoked brain potentials consistent with improved attention or memory processing. These effects appear to be due to raised brain insulin levels. Peripheral levels of Insulin Growth Factor‐I (IGF‐I) are associated with glucose regulation and influence glucose disposal. There is some indication that reduced sensitivity to insulin or IGF‐I in the brain, as observed in aging, obesity, and diabetes, decreases the clearance of Aβ amyloid. Such a decrease involves the insulin receptor cascade and can also increase amyloid toxicity. Insulin and IGF‐I may modulate brain levels of insulin degrading enzyme, which would also lead to an accumulation of Aβ amyloid.
Response to Novelty Correlates with Learning Rate in a Go/No‐Go Task in Göttingen Minipigs
Authors: Lind Nanna Marie , Moustgaard Anette
Published: March 2007

Novelty‐seeking and harm‐avoidance personality traits influence Go/No‐go (GNG) learning in humans. Animal studies have also indicated a link between response to novelty and spatial discrimination learning. In the present study, we test the hypothesis that learning rate in a GNG task correlates with the behavioral response of Göttingen minipigs to novelty. In a group of 12 minipigs of mixed genders, response to novelty was measured by numbers of contacts with a novel object, and the total duration of exploration of the novel object. These parameters were correlated to individual learning rate in a GNG task. The number of sessions to reach criterion in the GNG task correlated significantly with the number of contacts to a novel object (r = 0.70, p = 0.03), but not with the duration of object exploration (r = 0.29, p = 0.41). Thus, pigs with a low behavioral response to novelty learned the GNG task faster than did pigs with a strong behavioral response to novelty, indicated by the tendency to approach novel objects. We hypothesize that the critical factor in this relation is difference in emotional reactivity rather than difference in motivation for exploration. In conclusion, in addition to ‘cognitive’ ability, ‘temperamental’ factors are likely to influence learning in individual pigs.
Multi‐Joint Dynamics and the Development of Movement Control
Authors: Otten E.
Published: March 2007

The movement control of articulated limbs in humans has been explained in terms of equilibrium points and moving equilibrium points or virtual trajectories. One hypothesis is that the nervous system controls multi‐segment limbs by simply planning in terms of these equilibrium points and trajectories. The present paper describes a planar computer simulation of an articulated three‐segment limb, controlled by pairs of muscles. The shape of the virtual trajectory is analyzed when the limb is required to make fast movements with endpoint movements along a straight line with bell‐shaped velocity profiles. Apparently, the faster the movement, the more the virtual trajectory deviates from the real trajectory and becomes up to eight times longer. The complexity of the shape of the virtual trajectories and its length in these fast movements makes it unlikely that the nervous system plans using these trajectories. it seems simpler to set up the required bursts of muscle activation, coupled in the nervous system to the direction of movement, the s peed, and the place in workspace. Finally, it is argued that the two types of explanation do not contradict each other: when a relation is established in the nervous system between muscle activation and movements, equilibrium points and virtual trajectories are necessarily part of that relation.
Development of Postural Control During the First 18 Months of Life
Authors: Hadders-Algra Mijna
Published: March 2007

The present paper reviews the development of postural adjustments during infancy. In the control of posture, two functional levels can be distinguished. The basic level deals with the generation of direction‐specific adjustments meaning that dorsal muscles are primarily activated when the body sways forward, whereas ventral muscles are primarily activated when the body sways backward. The second level is involved in adaptation of the direction‐specific adjustments. Postural development starts with a repertoire of direction‐specific adjustments suggesting that the basic level of control has an innate origin. At first, during the phase of primary variability, postural activity is largely variable and can be minimally adapted to environmental constraints. At 3 months, postural activity shows a transient period during which few postural muscles participate in postural activity. From 6 months onward, the phase of secondary variability starts, during which the second level of postural control becomes functionally active and infants develop the ability to adapt postural activity to the specifics of the situation. Initially, adaptation can be accomplished in a simple way only, but from 9–10 months onward, it can be performed by the subtle adaptation of the degree of muscle contraction. Around 13–14 months, anticipatory postural adjustments emerge. It is concluded that the development of postural adjustments is characterized by four periods of transition occurring at the ages of 3, 6, 9‐10, and 13‐14 months. The major transition occurs at 6 months, when infants move from the phase of non‐adaptive, primary variability to the phase of adaptive, secondary variability.
Radionuclide Therapy of HER2-Positive Microxenografts Using a 177Lu-Labeled HER2-Specific Affibody Molecule
Authors: Tolmachev Vladimir , Orlova Anna , Pehrson Rikard , Galli Joakim , Baastrup Barbro , Andersson Karl , Sandström Mattias , Rosik Daniel , Carlsson Jörgen , Lundqvist Hans , Wennborg Anders , Nilsson Fredrik Y.
Published: March 2007

A radiolabeled anti-HER2 Affibody molecule (ZHER2:342) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (∼7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (ZHER2:342)2 was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A″-DTPA and labeled with the low-energy β-emitter 177Lu. The obtained conjugate [CHX-A″-DTPA-ABD-(ZHER2:342)2] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (ZHER2:342)2. Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq 177Lu-CHX-A″-DTPA-ABD-(ZHER2:342)2 completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non–HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight 177Lu-CHX-A″-DTPA-ABD-(ZHER2:342)2 as a candidate for treatment of disseminated tumors with a high level of HER2 expression. [Cancer Res 2007;67(6):2773–82]
MYCN-Directed Centrosome Amplification Requires MDM2-Mediated Suppression of p53 Activity in Neuroblastoma Cells
Authors: Slack Andrew D. , Chen Zaowen , Ludwig Andrew D. , Hicks John , Shohet Jason M.
Published: March 2007

The MYC family oncogenes cause transformation and tumor progression by corrupting multiple cellular pathways, altering cell cycle progression, apoptosis, and genomic instability. Several recent studies show that MYCC (c-Myc) expression alters DNA repair mechanisms, cell cycle checkpoints, and karyotypic stability, and this is likely partially due to alterations in centrosome replication control. In neuroblastoma cell lines, MYCN (N-Myc) expression induces centrosome amplification in response to ionizing radiation. Centrosomes are cytoplasmic domains that critically regulate cytokinesis, and aberrations in their number or structure are linked to mitotic defects and karyotypic instability. Whereas centrosome replication is linked to p53 and Rb/E2F-mediated cell cycle progression, the mechanisms downstream of MYCN that generate centrosome amplification are incompletely characterized. We hypothesized that MDM2, a direct transcriptional target of MYCN with central inhibitory effects on p53, plays a role in MYC-mediated genomic instability by altering p53 responses to DNA damage, facilitating centrosome amplification. Herein we show that MYCN mediates centrosome amplification in a p53-dependent manner. Accordingly, inhibition of the p53-MDM2 interaction with Nutlin 3A (which activates p53) completely ablates the MYCN-dependent contribution to centrosome amplification after ionizing radiation. We further show that modulating MDM2 expression levels by overexpression or RNA interference–mediated posttranscriptional inhibition dramatically affects centrosome amplification in MYCN-induced cells, indicating that MDM2 is a necessary and sufficient mediator of MYCN-mediated centrosome amplification. Finally, we show a significant correlation between centrosome amplification and MYCN amplification in primary neuroblastoma tumors. These data support the hypothesis that elevated MDM2 levels contribute to MYCN-induced genomic instability through altered regulation of centrosome replication in neuroblastoma. [Cancer Res 2007;67(6):2448–55]
Molecular Cloning of hMena (ENAH) and Its Splice Variant hMena+11a: Epidermal Growth Factor Increases Their Expression and Stimulates hMena+11a Phosphorylation in Breast Cancer Cell Lines
Authors: Di Modugno Francesca , DeMonte Lucia , Balsamo Michele , Bronzi Giovanna , Nicotra Maria Rita , Alessio Massimo , Jager Elke , Condeelis John S. , Santoni Angela , Natali Pier Giorgio , Nisticò Paola
Published: March 2007

hMena (ENAH), an actin regulatory protein involved in the control of cell motility and adhesion, is modulated during human breast carcinogenesis. In fact, whereas undetectable in normal mammary epithelium, hMena becomes overexpressed in high-risk benign lesions and primary and metastatic tumors. In vivo, hMena overexpression correlates with the HER-2+/ER−/Ki67+ unfavorable prognostic phenotype. In vitro, neuregulin-1 up-regulates whereas Herceptin treatment down-modulates hMena expression, suggesting that it may couple tyrosine kinase receptor signaling to the actin cytoskeleton. Herein, we report the cloning of hMena and of a splice variant, hMena+11a, which contains an additional exon corresponding to 21 amino acids located in the EVH2 domain, from a breast carcinoma cell line of epithelial phenotype. Whereas hMena overexpression consistently characterizes the transformed phenotype of tumor cells of different lineages, hMena+11a isoform is concomitantly present only in epithelial tumor cell lines. In breast cancer cell lines, epidermal growth factor (EGF) treatment promotes concomitant up-regulation of hMena and hMena+11a, resulting in an increase of the fraction of phosphorylated hMena+11a isoform only. hMena+11a overexpression and phosphorylation leads to increased p42/44 mitogen-activated protein kinase (MAPK) activation and cell proliferation as evidenced in hMena+11a–transfected breast cancer cell lines. On the contrary, hMena knockdown induces reduction of p42/44 MAPK phosphorylation and of the proliferative response to EGF. The present data provide new insight into the relevance of actin cytoskeleton regulatory proteins and, in particular, of hMena isoforms in coupling multiple signaling pathways involved in breast cancer. [Cancer Res 2007;67(6):2657–65]
Epigenetic Regulation of the Human Retinoblastoma Tumor Suppressor Gene Promoter by CTCF
Authors: De La Rosa-Velázquez Inti A. , Rincón-Arano Héctor , Benítez-Bribiesca Luis , Recillas-Targa Félix
Published: March 2007

Epigenetic misregulation is a more common feature in human cancer than previously anticipated. In the present investigation, we identified CCCTC-binding factor (CTCF), the multivalent 11-zinc-finger nuclear factor, as a regulator that favors a particular local chromatin conformation of the human retinoblastoma gene promoter. We show that its binding contributes to Rb gene promoter epigenetic stability. Ablation of the CTCF binding site from the human Rb gene promoter induced a rapid epigenetic silencing of reporter gene expression in an integrated genome context. CTCF DNA binding is methylation sensitive, and the methylated Rb-CTCF site is recognized by the Kaiso methyl-CpG–binding protein. This is the first evidence suggesting that CTCF protects the Rb gene promoter, a classic CpG island, against DNA methylation, and when such control region is abnormally methylated Kaiso, and probably its associated repressor complex, induce epigenetic silencing of the promoter. Our results identify CTCF as a novel epigenetic regulator of the human retinoblastoma gene promoter. [Cancer Res 2007;67(6):2577–85]