bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct Contributions of Median Raphe Nucleus to ContextualFear Conditioning and Fear‐Potentiated Startle
Authors: Silva R. C. B. , Cruz A. P. M. , Avanzi V. , Landeira-Fernandez J. , Brandão M. L.
Published: March 2007

Ascending 5‐HT projections from the
median raphe nucleus (MRN), probably to the
hippocampus, are implicated in the acquisition
of contextual fear (background stimuli), as
assessed by freezing behavior. Foreground cues
like light, used as a conditioned stimulus (CS) in
classical fear conditioning, also cause freezing
through thalamic transmission to the amygdala.
As the MRN projects to the hippocampus and
amygdala, the role of this raphe nucleus in fear
conditioning to explicit cues remains to be
explained. Here we analyzed the behavior of
rats with MRN electrolytic lesions in a
contextual conditioning situation and in a fear‐potentiated
startle procedure. The animals
received MRN electrolytic lesions either before
or on the day after two consecutive training
sessions in which they were submitted to 10
conditioning trials, each in an experimental
chamber (same context) where they. received
foot‐shocks (0.6 mA, 1 sec) paired to a 4‐sec
light CS. Seven to ten days later, the animals
were submitted to testing sessions for assessing
conditioned fear when they were placed for five
shocks, and the duration of contextual freezing
was recorded. The animals were then submitted
to a fear‐potentiated startle in response to a 4‐sec
light‐CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same
context showed more freezing than did rats
with pre‐ or post‐training MRN lesions. Startle
was clearly potentiated in the presence of light CS in the sham‐lesioned animals. Whereas pretraining
lesions reduced both freezing and fear‐potentiated
startle, the post‐training lesions
reduced only freezing to context, without
changing the fear‐potentiated startle. In a
second experiment, neurotoxic lesions of the
MRN with local injections of N‐methyl‐D‐aspartate
or the activation of 5‐HT1A somatodendritic
auto‐receptors of the MRN by
microinjections of the 5‐HT1A receptor agonist
8‐hydroxy‐ 2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT)
before the training sessions also reduced
the amount of freezing and the fear‐potentiated
startle. Freezing is a prominent response of
contextual fear conditioning, but does not seem
to be crucial for the enhancement of the startle
reflex by explicit aversive cues. As fear‐potentiated
startle may be produced in posttraining
lesioned rats that are unable to freeze
to fear contextual stimuli, dissociable systems
seem to be recruited in each condition. Thus,
contextual fear and fear‐potentiated startle are
conveyed by distinct 5‐HT‐mediated circuits of
the MRN.
Slow Late Component in Conditioned Stimulus‐Evoked PotentialsFrom the Amygdala After Fear Conditioning in the Rat
Authors: Knippenberg J. M. J. , van Luijtelaar E. L. J. M. , Maes J. H. R.
Published: March 2007

Male Wistar rats were subjected to a
differential Pavlovian fear conditioning procedure
in which one of two tones (6 or 10 kHz)
was followed by an electric shock (CS+) and the
other was not (CS−). Before and after fear
conditioning, we recorded the evoked potentials
elicited by CS+ and CS− from electrodes aimed at
the lateral nucleus of the amygdala. Before
conditioning, a slow, negative component with
peak amplitude around 150 ms was present in
the evoked potentials. This component was
sensitive to habituation. After fear conditioning,
both CS+ and CS− elicited the same late
component, albeit with a larger amplitude. This
enhancement was temporary: decreasing
amplitude was observed in the course of CS test
presentations under extinction. Prior research
revealed a comparable slow component in the
amygdala of the cat under similar experimental
conditions. The collective results indicate that
the large late component in the amygdala is
enhanced by fear conditioning, suggesting that
such enhancement reflects the anticipation of a
biologically significant event.
Vision After Early-Onset Lesions of the Occipital Cortex:II. Physiological Studies
Authors: Knyazeva M. G. , Maeder P. , Kiper D. C. , Deonna T. , Innocenti G. M.
Published: March 2007

In one of two patients (MS and FJ) with
bilateral, early‐onset lesion of the primary
visual cortex, Kiper et al. (2002) observed
a considerable degree of functional recovery. To
clarify the physiological mechanisms involved
in the recovery, we used fMRI and quantitative
EEG to study both patients. The fMRI
investigations indicated that in both patients,
isolated islands of the primary visual cortex are
functioning, in the right hemisphere in MS and
in the left in FJ. The functional recovery
observed in MS roughly correlated with the
functional maturation of interhemispheric
connections and might reflect the role of corticocortical connectivity in visual perception. The
functionality of interhemispheric connections
was assessed by analyzing the changes in
occipital inter‐hemispheric coherence of EEG
signals (ICoh) evoked by moving gratings. In
the patient MS, this ICoh response was present
at 7:11 y and was more mature at 9:2 y. In the
more visually mpaired patient, FJ, a consistent
increase in ICoh to visual stimuli could not be
obtained, possibly because of the later occurrence
of the lesion.
Recovery from Lesion‐Associated Learning Deficits by Fetal Amygdala Transplants
Authors: Jain Suman , Mathur Rashmi , Sharma Ratna , Nayar Usha
Published: March 2007

Bilateral lesions of the amygdaloid complex
result in elimination or attenuation of the
conditioned freezing that is normally seen in the
conditioned emotional response (CER) paradigm
and the active avoidance (AA) task. We observed
the effect of amygdalar tissue transplantation
on the ability of lesioned (central nucleus of
amygdala, CeA) rats to learn CER and AA. In
two groups of adult Wistar rats, sham operation
or bilateral lesions of the CeA were produced
electrolytically (2mA for 8 sec). In a third group,
fetal amygdalar tissue was transplanted at the
CeA‐lesioned site 2 d postoperatively. All rats
were trained on CER and AA from the 6th postoperative day. In comparison with the shamoperated
group, bilaterally CeA‐lesioned rats
showed a significant (p < 0.001) increase in all
CER scores, indicating an acquisition deficit.
After fetal amygdalar tissue transplantation,
the CER scores significantly decreased (p < 0.05) when compared with the lesioned group. A
significant (p < 0.01) decrease in the percentage
of avoidance in the AA task occurring after
CeA lesion returned to control values after
amygdalar tissue transplantation. In conclusion,
in CeA‐lesioned rats a complete behavioral
deficit in learning CER and AA was restored by
transplanting fetal amygdalar tissue at the
lesioned site.
Effectiveness of Neuromotor Task Training for Children with Developmental Coordination Disorder: A Pilot Study
Authors: Schoemaker M. M. , Niemeijer A. S. , Reynders K. , Smits-Engelsman B. C. M.
Published: March 2007

The aim of this pilot study was to evaluate
the effectiveness of a Neuromotor Task
Training (NTT), recently developed for the
treatment of children with Developmental
Coordination Disorder (DCD) by pediatric
physical therapists in the Netherlands. NTT is
a task‐oriented treatment program based
upon recent insights from motor control and
motor learning research. Ten children with
DCD (intervention group) were tested before
and after 9 and 18 treatment sessions on the
Movement ABC and a dysgraphia scale in
order to measure the effectiveness of
treatment on gross and fine motor skills in
general and handwriting in particular. Five
children (no‐treatment control group) were
tested twice with a time lag of nine weeks on
the Movement ABC in order to measure
spontaneous improvement. No improvement
was measured for the children in the notreatment
control group, whereas a significant
improvement was found for children in the
intervention group for both quality of
handwriting and performance on the
Movement ABC after 18 treatment sessions.
Cerebellar and Hippocampal Activation During Eyeblink Conditioning Depends on the Experimental Paradigm: A MEG Study
Authors: Kirsch Peter , Achenbach Caroline , Kirsch Martina , Heinzmann Matthias , Schienle Anne , Vaitl Dieter
Published: March 2007

The cerebellum and the hippocampus are
key structures for the acquisition of conditioned
eyeblink responses. Whereas the cerebellum
seems to be crucial for all types of eyeblink
conditioning, the hippocampus appears to be
involved only in complex types of learning. We
conducted a differential conditioning study to
explore the suitability of the design for
magnetencephalography (MEG). In addition,
we compared cerebellar and hippocampal
activation during differential delay and trace
conditioning. Comparable conditioning effects
were seen in both conditions, but a greater
resistance to extinction for trace conditioning.
Brain activation differed between paradigms:
delay conditioning provoked activation only in
the cerebellum and trace conditioning only in
the hippocampus. The results reflect differential
brain activation patterns during the two types
of eyeblink conditioning.
Effects of Early Training and Nicotine Treatment on thePerformance of Male NMRI Mice in the Water Maze
Authors: Vicens Paloma , Carrasco M. Carmen , Redolat Rosa
Published: March 2007

This research aimed to evaluate the effect of
nicotine treatment and prior training on a
spatial learning task in differently aged NMRI
male mice. In a longitudinal study, mice were
randomly assigned to one of 14 experimental
groups receiving different combinations of
chronically injected nicotine (0.35 mg/kg)
administered for 10 days (5 days before and
during 5 days acquisition of task) or control
treatments and training in the water maze at
different ages. The mice displayed shorter
escape latencies when evaluated at 6 and 10
months than when tested in this task at 2
months for the first time, demonstrating that
early training preserves performance in the
water maze up to 8 months after the initial
experience. Nicotine treatment did not
significantly change performance in the water
maze at any age tested. Early practice in a
spatial reference memory task appears to have
lasting consequences and can potentially
contribute to preventing some age‐related
spatial learning deficits.
Neonatal Brain MRI and Motor Outcome at School Age in Childrenwith Neonatal Encephalopathy: A Review of Personal Experience
Authors: Mercuri Eugenio , Barnett Anna L.
Published: March 2007

The aim of this paper is to review (i) the
spectrum of neuromotor function at school age in
children who had been born full‐term and
presented with neonatal encephalopathy (NE) and
low Apgar scores and (ii) the relation between the
presence/absence of such difficulties and neonatal
brain MRI. Motor outcome appears to be mainly
related to the severity of basal ganglia and
internal capsule involvement. Severe basal ganglia
lesions were always associated with the most
severe outcome, microcephaly, tetraplegia, and
severe global delay, whereas more discrete basal
ganglia lesions were associated with athetoid
cerebral palsy, with normal cognitive development
or minor neuro‐motor abnormalities. White
matter lesions were associated with abnormal
motor outcome only if the internal capsule was
involved. Children with moderate white matter
changes but normal internal capsule, had normal
motor outcome at school age.
Why Bother About Clumsiness? The Implications of HavingDevelopmental Coordination Disorder (DCD)
Authors: Gillberg Christopher , Kadesjö Björn
Published: March 2007

Developmental coordination disorder (DCD)
is a common motor problem affecting—even in
rather severe form—several percent of school
age children. In the past, DCD has usually been
called ‘clumsy child syndrome’ or ‘non‐cerebralpalsy
motor‐perception dysfunction’. This
disorder is more common in boys than in girls
and is very often associated with psychopathology,
particularly with attention‐deficit/hyperactivity
disorder (ADHD) and autism spectrum disorders/
autistic‐type problems. Conversely, children
with ADHD and autism spectrum problems,
particularly those given a diagnosis of Asperger
syndrome, have a very high rate of comorbid
DCD. Psychiatrists appear to be unaware of this
type of comorbidity in their young patients.
Neurologists, on the other hand, usually pay
little attention to the striking behavioral and
emotional problems shown by so many of their
‘clumsy’ patients. A need exists for a much
clearer focus on DCD—in child psychiatry and
in child neurology—both in research and in
clinical practice.
Complete and Partial Lesions of the Pyramidal Tract in theRat Affect Qualitative Measures of Skilled Movements:Impairment in Fixations as a Model for Clumsy Behavior
Authors: Whishaw Ian Q. , Piecharka Dionne M. , Drever Felicia R.
Published: March 2007

Little is known about prenatal and perinatal
brain injury resulting in subsequent clumsy
behavior in children. One candidate motor system
is the pyramidal tract. The tract traverses the
entire central nervous system and, through direct
and indirect connections to the brainstem and
spinal cord sensory and motor nuclei, is involved
in the learning and execution of skilled movements.
Here, rats, either naive or pretrained on a
number of motor tasks, were assessed for acute
and chronic impairments following complete or
incomplete pyramidal tract lesions. Postsurgery
rats with complete lesions were impaired on the
qualitative measures of limb aiming, supination,
and posture. Impaired movements require
fixations, complementary movements in different
body segments. The impairment in fixations was
manifest acutely and underwent no improvement
with subsequent training/testing. The finding that
complete and partial pyramidal tract lesions
produce chronic impairment in fixations provides
insight for understanding clumsy behavior in
humans and its potential remediation via specific
training in making fixations.
Inhibitory Deficits, Delay Aversion and Preschool AD/HD:Implications for the Dual Pathway Model
Authors: Dalen Lindy , Sonuga-Barke Edmund J. S. , Hall Martin , Remington Bob
Published: March 2007

The dual pathway model proposes the existence of separate and neurobiologically distinct cognitive (inhibitory and more general executive dysfunction) and motivational (delay aversion) developmental routes to AD/HD. The study reported in this paper explores the relation between inhibitory deficits and delay
aversion and their association with AD/HD in a group of three‐year‐old children. Children identified as having a pre‐school equivalent of AD/HD (N=19) and controls (N=19), matched for gender and IQ, completed a battery of inhibition and delay tasks. Correlational and factor analysis supported a dissociation between inhibitory deficits (go‐no‐go, set shifting) and delay aversion (choice delay) with delay of gratification cross‐loading. Children
with AD/HD displayed more inhibitory deficits and were more delay averse than controls. The data support the value of the distinction between motivational and cognitive pathways to AD/HD. Furthermore, the data suggest that
such a distinction is apparent relatively early on during development.
Dopamine Appetite and Cognitive Impairment in Attention Deficit/Hyperactivity Disorder
Authors: Williams Jonathan , Taylor Eric
Published: March 2007

The underlying defects in ADHD (Attention
Deficit/Hyperactivity Disorder) are not yet clear.
The current paper tests three existing theories:
State Regulation, Cognitive Deficit, and
Temporal Difference (TD) learning. We present
computational simulations of the Matching
Familiar Figures Task and compare these with
the experimental results reported by Sonuga‐
Barke (2002). The TD model contains four
parameters: the learning rate, discounting for
future rewards, brittleness (randomness) of
behavior, and action bias. The results show that
the basic TD model accounts well for control
performance in trials of 5 sec, 10 sec, and 15 sec
duration; but not for the deficits in ADHD
performance at 5 sec and 15 sec. Extending the
TD model to incorporate either a state
regulation deficit, or working memory deficit
and delay in starting trials, can provide a good
account of both control and ADHD results, at
all trial‐lengths. We discuss the significance of
the results for theories of ADHD and make
suggestions for future experimentation.
Involvement of Norepinephrine in the Control of Activity and Attentive Processes in Animal Models of Attention Deficit Hyperactivity Disorder
Authors: Viggiano D. , Ruocco L. A. , Arcieri S. , Sadile A. G.
Published: March 2007

Functional and morphological studies in
children affected by Attention Deficit Hyperactivity
Disorder (ADHD) suggest a prefrontal
cortex (PFc) dysfunction. This cortical region is
regulated by subcortical systems including noradrenergic
(NEergic), dopaminergic (DAergic),
cholinergic, serotonergic, and histaminergic pathways.
A wealth of data in humans and in animal
models demonstrates altered dopamine (DA)
regulation. Drugs that modulate norepinephrine
(NE) transmission are also effective in ADHD
patients, thus leading to the hypothesis of a
NEergic disorder. This review covers the
regulation of PFc functions by NE and the
interaction between the NE and DA systems, as
suggested by pharmacological, electrophysiological,
morphological, and gene knock out (KO)
studies. A negative feedback between NE and DA
neurons emerges from KO studies because KO
mice showing increased (NE transporter (NET)
KO) or decreased (DBH and VMAT2 KO) NE
levels are respectively associated with lower and
higher DA levels. Locomotor activity can be
generally predicted by the DA level, whereas
sensitivity to amphetamines is by NE/DA balance.
Some animal models of ADHD, such as
spontaneously hypertensive rats (SHR), show
alterations in the PFc and in the DA system.
Evidence about a correlation between the NE
system and hyper‐locomotion activity in such
animals has not yet been clarified. Therefore, this
review also includes recent evidence on the
behavioral effects of two NET blockers,
reboxetine and atomoxetine, in two animal models
of ADHD: SHR and Naples High Excitability rats.
As these drugs modulate the DA level in the PFc,
certain effects are likely to be due to a rebalanced
DA system. We discuss the significance of the
results for theories of ADHD and make
suggestions for future experimentation.
On the Reorganization of Incentive Structure to PromoteDelay Tolerance: A Therapeutic Possibility for AD/HD?
Authors: Sonuga-Barke Edmund J. S.
Published: March 2007

This paper brings together two recent insights into attention deficit/hyperactivity disorder (AD/HD) to provide the rationale for a novel approach to treatment. First is the suggestion, backed up by data from randomized
trials, that training and practice in carefully selected cognitive activities (executive and attentional training) and tasks can provide a way of modifying the processes underlying cognitive, especially executive, deficits in
AD/HD. Second, is the idea that AD/HD is a neuropsychologically heterogeneous disorder resulting from motivational alterations, specifically an increased intolerance for delay, as well as executive deficits. The paper builds
on these two insights to explore the possibility that the motivational alterations underpinning delay aversion can be modified through specific training regimes in a way equivalent to that found with executive and attentional training. The requirements for such an approach are set out. Delay fading is proposed as a possible basis for reorganizing delay experience, altering the incentive value of delay (e.g., increasing tolerance for delay), thereby reducing AD/HD symptoms.
Enhancement of Dopaminergic Differentiation in Proliferating Midbrain Neuroblasts by Sonic Hedgehog and Ascorbic Acid
Authors: Volpicelli Floriana , Consales Claudia , Caiazzo Massimiliano , Colucci-D′Amato Luca , Perrone-Capano Carla , di Porzio Umberto
Published: March 2007

We analyzed the molecular mechanisms
involved in the acquisition and maturation of
dopaminergic (DA) neurons generated in vitro
from rat ventral mesencephalon (MES) cells in the
presence of mitogens or specific signaling
molecules. The addition of basic fibroblast growth
factor (bFGF) to MES cells in serum‐free medium
stimulates the proliferation of neuroblasts but
delays DA differentiation. Recombinant Sonic
hedgehog (SHH) protein increases up to three fold
the number of tyrosine hydroxylase (TH)‐positive
cells and their differentiation, an effect abolished
by anti‐SHH antibodies. The expanded cultures
are rich in nestin‐positive neurons, glial cells are
rare, all TH+ neurons are DA, and all DA and
GABAergic markers analyzed are expressed.
Adding ascorbic acid to bFGF/SHH‐treated
cultures resulted in a further five‐ to seven‐fold
enhancement of viable DA neurons. This
experimental system also provides a powerful tool
to generate DA neurons from single embryos. Our
strategy provides an enriched source of MES DA
neurons that are useful for analyzing molecular
mechanisms controlling their function and for
experimental regenerative approaches in DA
dysfunction.
Development of Postural Control in Healthy Children: A Functional Approach
Authors: Assaiante Christine , Mallau Sophie , Viel Sébastien , Jover Marianne , Schmitz Christina
Published: March 2007

From a set of experimental studies showing how intersegmental coordination develops during childhood in various posturokinetic tasks, we have established a repertoire of equilibrium strategies in the course of ontogenesis. The experimental data demonstrate that the first reference frame used for the organization of balance control during locomotion is the pelvis, especially in young children. Head stabilization during posturokinetic activities, particularly locomotion, constitutes a complex motor skill requiring a long time to develop during childhood. When studying the emergence of postural strategies, it is essential to distinguish between results that can be explained by biomechanical reasons strictly and those reflecting the maturation of the central nervous system (CNS). To address this problem, we have studied our young subjects in situations requiring various types of adaptation. The studies dealing with adaptation of postural strategies aimed at testing short and long‐term adaptation capacity of the CNS during imposed transient external biomechanical constraints in healthy children, and during chronic internal constraints in children with skeletal pathologies. In addition to maintenance of balance, another function of posture is to ensure the orientation of a body segment. It appears that the control of orientation and the control of balance both require the trunk as an initial reference frame involving a development from egocentric to exocentric postural control. It is concluded that the first step for children consists in building a repertoire of postural strategies, and the second step consists in learning to select the most appropriate postural strategy, depending on the ability to anticipate the consequence of the movement in order to maintain balance control and the efficiency of the task.
Perinatal Development of the Motor Systems Involved in Postural Control
Authors: Vinay Laurent , Ben-Mabrouk Faïza , Brocard Frédéric , Clarac François , Jean-Xavier Céline , Pearlstein Edouard , Pflieger Jean-François
Published: March 2007

Motor behaviors of some species, such as the rat and the human baby, are quite immature at birth. Here we review recent data on some of the mechanisms underlying the postnatal maturation of posture in the rat, in particular the development of pathways descending from the brain stem and projecting onto the lumbar enlargement of the spinal cord. A short‐lasting depletion in serotonin affects both posture and the excitability of motoneurons. Here we try to extrapolate to human development and suggest that the abnormalities in motor control observed in childhood—e.g, deficits in motor coordination—might have their roots in the prenatal period, in particular serotonin depletion due to exposure to several environmental and toxicological factors during pregnancy.
Role of the Basal Ganglia in Balance Control
Authors: Visser Jasper E. , Bloem Bastiaan R.
Published: March 2007

In this review paper, we summarize the important contributions of the basal ganglia to the regulation of postural control. After a brief overview of basal ganglia circuitries, the emphasis is on clinical observations in patients with focal lesions in parts of the basal ganglia, as the impairments seen here can serve to highlight the normal functions of the basal ganglia nuclei in postural control. Two particularly relevant functions are discussed in detail: first, the contribution of the basal ganglia to flexibility and to gaining control of balancecorrecting responses, including the ability to lend priority to the elements of a postural task; and second, processing afferent information by the basal ganglia, which is increasingly recognized as being highly relevant for postural control.
Postural Muscle Dyscoordination in Children With Cerebral Palsy
Authors: van der Heide Jolanda C. , Hadders-Algra Mijna
Published: March 2007

The present paper gives an overview of the knowledge currently available on muscular dyscoordination underlying postural problems in children with cerebral palsy (CP). Such information is a prerequisite for developing successful therapeutic interventions in children with CP. Until now, three children with CP functioning at GMFCS (Gross Motor Function Classification System) level V have been documented. The children totally or partially lacked direction specificity in their postural adjustments and could not sit independently for more than 3 seconds. Some children functioning at GMFCS level IV have intact direction‐specific adjustments, whereas others have problems in generating consistently direction‐specific adjustments. Children at GMFCS levels I to III have an intact basic level of control but have difficulties in fine‐tuning the degree of postural muscle contraction to the task‐specific conditions, a dysfunction more prominently present in children with bilateral spastic CP than in children with spastic hemiplegia. The problems in the adaptation of the degree of muscle contraction might be the reason that children with CP, more often than typically developing children, show an excess of antagonistic coactivation during difficult balancing tasks and a preference for cranial‐caudal recruitment during reaching. This might imply that both stereotypies might be regarded as functional strategies to compensate for the dysfunctional capacity to modulate subtly postural activity.
Role of Visual Dysfunction in Postural Control in Children With Cerebral Palsy
Authors: Porro G. , van der Linden D. , van Nieuwenhuizen O. , Wittebol-Post D.
Published: March 2007

Introduction: Deficient postural control is one of the key problems in cerebral palsy (CP). Little, however, is known about the specific nature of postural problems of children with CP, nor of the relation between abnormal posture and dysfunction of the visual system. Aim of the study: To provide additional information on the association of abnormalities in postural control and visual dysfunction of the anterior or posterior part of the visual system. Methods: Data resulting from ophthalmologic, orthoptic, neurological, neuro‐radiological, and ethological investigations of more than 313 neurologically impaired children were retrospectively analyzed. Results: Abnormal postural control related to ocular and ocular motor disorders consisted of anomalous head control and subsequent abnormal head posture and torticollis. The abnormal postural control related to retrochiasmatical damage of the visual system consisted of a torticollis combined with adjustment of the upper part of the body, as if at the same time adapting to a combination of defects and optimizing residual visual functions. Conclusion: Visual dysfunctions play a distinct role in the postural control of children with CP.
Postural Dysfunction in Children With Cerebral Palsy: Some Implications for Therapeutic Guidance
Authors: Carlberg Eva Brogren , Hadders-Algra Mijna
Published: March 2007

Postural problems play a central role in the motor dysfunction of children with cerebral palsy (CP). Therefore, they spend more time in sitting than in standing to perform vital tasks of daily life. The focus of this article is to describe the pathophysiology of postural control in sitting and outline some implications for management and treatment. In general, children with CP exhibit muscular activity counteracting forces that disturb equilibrium. Only ‘non‐sitting’ children with severe CP lack such ‘direction‐specific’ adjustments, possibly ruling out achievement of independent sitting. Most frequently, the children display dysfunctions in the adaptation of the adjustment. Typical characteristics of this adaptation in children with CP are a top‐down recruitment of pos tural muscles, an excessive degree of antagonistic coactivation, and an incomplete adaptation of the EMG‐amplitude to task specific constraints. Despite our knowledge on the pathophysiology underlying the postural problems in children with CP, little ’high‐level’ evidence (according to Sackett) exists on how different interventions can affect these problems. Therapeutic attention to promote motor performance in sitting focuses on adaptive seating, tilting of the support surface, and ample, variable training in motivating settings. The challenge facing us now is to provide evidence about the efficacy of specific treatment approaches facilitating that children reach an optimal level of functioning in daily life.
Efficacy and Effectiveness of Physical Therapy in Enhancing Postural Control in Children With Cerebral Palsy
Authors: Harris Susan R. , Roxborough Lori
Published: March 2007

The purpose of this article was to conduct a systematic review of studies that examined the efficacy and effectiveness of postural control intervention strategies for children with CP. Only physical therapy interventions were included, e.g. adaptive seating devices, ankle foot orthoses, neurodevelopmental treatment. A multifaceted search strategy was employed to identify all potential studies published between 1990 and 2004. The search strategy included electronic databases, reference list scanning, author and citation tracking of relevant studies, and hand searching of pediatric physical therapy journals and conference proceedings. Twelve studies (1991–2004), comprising ten group design studies and two single subject studies, met our inclusion criteria. A variety of age ranges and severity of children with cerebral palsy (n = 132) participated in the studies. The study quality scores ranged from 2 to 7 (total possible range of 0 to 7) with a median score of 5.5 and a mode of 6. As was true in an earlier systematic review on adaptive seating, most of the 12 ‘experimental’ studies published since 1990 that were aimed at evaluating the effectiveness of postural control strategies provided lower levels of evidence, i.e. Sackett Levels III to V. Additional studies with stronger designs are needed to establish that postural control interventions for children with CP are effective.
Interaction Between Emotion and Memory: Importance of Mammillary Bodies Damage in a Mouse Model of the Alcoholic Korsakoff Syndrome
Authors: Béracochéa Daniel
Published: March 2007

Chronic alcohol consumption (CAC) can lead to the Korsakoff syndrome (KS), a memory deficiency attributed to diencephalie damage and/or to medial temporal or cortical related dysfunction. The etiology of KS remains unclear. Most animal models of KS involve thiaminedeficient diets associated with pyrithiamine treatment. Here we present a mouse model of CAC‐induced KS. We demonstrate that CAC‐generated retrieval memory deficits in working/ episodic memory tasks, together with a reduction of fear reactivity, result from damage to the mammillary bodies (MB). Experimental lesions of MB in non‐alcoholic mice produced the same memory and emotional impairments. Drugs having anxiogenic‐like properties counteract such impairments produced by CAC or by MB lesions. We suggest (a) that MB are the essential components of a brain network underlying emotional processes, which would be critically important in the retrieval processes involved in working/ episodic memory tasks, and (b) that failure to maintain emotional arousal due to MB damage can be a main factor of CAC‐induced memory deficits. Overall, our animal model fits well with general neuropsychological and anatomic impairments observed in KS.
Genetic Mouse Models of Alzheimer′s Disease
Authors: Mineur Yann S. , McLoughlin Declan , Crusio Wim E. , Sluyter Frans
Published: March 2007

In the current minireview, we focus on genetic mouse models of Alzheimer′s disease (AD). Because various excellent, up‐to‐date reviews, special issues, and reliable websites are already dedicated to the genetics of Alzheimer′s disease in general and of animal models in particular, this review is not meant to be comprehensive. Rather, we aim to steer the Alzheimer′s novice through the recent mouse literature on AD. Special attention will be paid to genetic models that have been tested behaviorally.
Erythropoietin Improves Place Learning in an 8‐Arm Radial Maze in Fimbria‐Fornix Transected Rats
Authors: Malá Hana , Alsina Carina Gili , Madsen Kathrine Skak , Sibbesen Else la Cour , Stick Henriette , Mogensen Jesper
Published: March 2007

Systemically administered human recombinant erythropoietin (EPO) may have the potential to reduce the cognitive and behavioral symptoms of mechanical brain injury. In a series of studies, we address this possibility. We previously found that EPO given to fimbriafornix transected rats at the moment of injury could substantially improve the posttraumatic acquisition of an allocentric place learning task when such a task is administered in a water maze. Due to the clinical importance of such results, it is important to scrutinize whether the therapeutic effect of EPO is specific to the experimental setup of our original experiments or generalizes across test situations. Consequently, here we studied the effects of similarly administered EPO in fimbria‐fornix transected and control operated rats, respectively, evaluating the posttraumatic behavioral/cognitive abilities in an allocentric place learning task administered in an 8‐arm radial maze. The administration of EPO to the hippocampally injured rats was associated with a virtually complete elimination of the otherwise severe behavioral impairment caused by fimbria‐fornix transection. In contrast, EPO had no detectable effect on the task acquisition of non‐lesioned animals. The results of the present study confirm our previous demonstration of EPO′s ability to reduce or eliminate the behavioral/cognitive consequences of mechanical injury to the hippocampus, while adding the important observation that such a therapeutic effect is not restricted to the specific experimental setup previously studied.
Postural Control in Man: The Phylogenetic Perspective
Authors: Gramsbergen Albert
Published: March 2007

Erect posture in man is a recent affordance from an evolutionary perspective. About eight million years ago, the stock from which modern humans derived split off from the ape family, and from around sixty‐thousand years ago, modern man developed. Upright gait and manipulations while standing pose intricate cybernetic problems for postural control. The trunk, having an older evolutionary history than the extremities, is innervated by medially descending motor systems and extremity muscles by the more recent, laterally descending systems. Movements obviously require concerted actions from both systems. Research in rats has demonstrated the interdependencies between postural control and the development of fluent walking. Only 15 days after birth, adult‐like fluent locomotion emerges and is critically dependent upon postural development. Vesttibular deprivation induces a retardation in postural development and, consequently, a retarded development of adult‐like locomotion. The cerebellum obviously has an important role in mutual adjustments in postural control and extremity movements, or, in coupling the phyiogenetic older and newer structures. In the human, the cerebellum develops partly after birth and therefore is vulnerable to adverse perinatal influences. Such vulnerability seems to justify focusing our scientific research efforts onto the development of this structure.
Dominant-Negative Activator Protein 1 (TAM67) Targets Cyclooxygenase-2 and Osteopontin under Conditions in which It Specifically Inhibits Tumorigenesis
Authors: Matthews Connie P. , Birkholz Alysia M. , Baker Alyson R. , Perella Christine M. , Beck George R. , Young Matthew R. , Colburn Nancy H.
Published: March 2007

Activation of activator protein 1 (AP-1) and nuclear factor κB (NFκB)–dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFκB activation by interacting with NFκB p65. Two-stage [7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14-HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67–expressing mice results in dramatic inhibition of tumor promoter–induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPA- or E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1– and/or NFκB-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA–induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NFκB sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter. [Cancer Res 2007;67(6):2430–8]
Anaplastic, Plasmablastic, and Plasmacytic Plasmacytomas of Mice: Relationships to Human Plasma Cell Neoplasms and Late-Stage Differentiation of Normal B Cells
Authors: Qi Chen-Feng , Zhou Jeff X. , Lee Chang Hoon , Naghashfar Zohreh , Xiang Shao , Kovalchuk Alexander L. , Fredrickson Torgny N. , Hartley Janet W. , Roopenian Derry C. , Davidson Wendy F. , Janz Siegfried , Morse Herbert C.
Published: March 2007

We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V+ congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-β2M−/− mice. NFS.V+ tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V+ and SJL-β2M−/− mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease. [Cancer Res 2007;67(6):2439–47]
Combining Adoptive Cellular and Immunocytokine Therapies to Improve Treatment of B-Lineage Malignancy
Authors: Singh Harjeet , Serrano Lisa Marie , Pfeiffer Timothy , Olivares Simon , McNamara George , Smith David D. , Al-Kadhimi Zaid , Forman Stephen J. , Gillies Stephen D. , Jensen Michael C. , Colcher David , Raubitschek Andrew , Cooper Laurence J.N.
Published: March 2007

Currently, the lineage-specific cell-surface molecules CD19 and CD20 present on many B-cell malignancies are targets for both antibody- and cell-based therapies. Coupling these two treatment modalities is predicted to improve the antitumor effect, particularly for tumors resistant to single-agent biotherapies. This can be shown using an immunocytokine, composed of a CD20-specific monoclonal antibody fused to biologically active interleukin 2 (IL-2), combined with ex vivo expanded human umbilical cord blood–derived CD8+ T cells, that have been genetically modified to be CD19 specific, for adoptive transfer after allogeneic hematopoietic stem-cell transplantation. We show that a benefit of targeted delivery of recombinant IL-2 by the immunocytokine to the CD19+CD20+ tumor microenvironment is improved in vivo persistence of the CD19-specific T cells, and this results in an augmented cell-mediated antitumor effect. Phase I trials are under way using anti-CD20-IL-2 immunocytokine and CD19-specific T cells as monotherapies, and our results warrant clinical trials using combination of these two immunotherapies. [Cancer Res 2007;67(6):2872–80]
Mullerian-Inhibiting Substance Induces Gro-β Expression in Breast Cancer Cells through a Nuclear Factor-κB–Dependent and Smad1-Dependent Mechanism
Authors: Gupta Vandana , Yeo Giminna , Kawakubo Hirofumi , Rangnekar Vivek , Ramaswamy Preethi , Hayashida Tetsu , MacLaughlin David T. , Donahoe Patricia K. , Maheswaran Shyamala
Published: March 2007

Mullerian-inhibiting substance (MIS), a transforming growth factor-β family member, activates the nuclear factor-κB (NF-κB) pathway and induces the expression of B-cell translocation gene 2 (BTG2), IFN regulatory factor-1 (IRF-1), and the chemokine Gro-β. Inhibiting NF-κB activation with a phosphorylation-deficient IκBα mutant abrogated MIS-mediated induction of all three genes. Expression of dominant-negative Smad1, in which serines at the COOH-terminal SSVS motif are converted to alanines, suppressed MIS-induced Smad1 phosphorylation and impaired MIS-stimulated Gro-β promoter-driven reporter expression and Gro-β mRNA. Suppressing Smad1 expression using small interfering RNA also mitigated MIS-induced Gro-β mRNA, suggesting that regulation of Gro-β expression by MIS was dependent on activation of NF-κB as well as Smad1. However, induction of IRF-1 and BTG2 mRNAs by MIS was independent of Smad1 activation. Characterization of κB-binding sequences within Gro-β, BTG2, and IRF-1 promoters showed that MIS stimulated binding of p50 and p65 subunits to all three sites, whereas phosphorylated Smad1 (phospho-Smad1) protein was detectable only in the NF-κB complex bound to the κB site of the Gro-β promoter. Consistent with these observations, chromatin immunoprecipitation assays showed recruitment of both phospho-Smad1 and p65 to the Gro-β promoter in vivo, whereas p65, but not phospho-Smad1, was recruited to the BTG2 promoter. These results show a novel interaction between MIS-stimulated Smad1 and NF-κB signaling in which enhancement of NF-κB DNA binding and gene expression by phospho-Smad1 is dependent on the sequence of the κB consensus site within the promoter. [Cancer Res 2007;67(6):2747–56]
Mutant p53 Enhances Nuclear Factor κB Activation by Tumor Necrosis Factor α in Cancer Cells
Authors: Weisz Lilach , Damalas Alexander , Liontos Michalis , Karakaidos Panagiotis , Fontemaggi Giulia , Maor-Aloni Revital , Kalis Marina , Levrero Massimo , Strano Sabrina , Gorgoulis Vassilis G. , Rotter Varda , Blandino Giovanni , Oren Moshe
Published: March 2007

Mutations in the p53 tumor suppressor are very frequent in human cancer. Often, such mutations lead to the constitutive overproduction of mutant p53 proteins, which may exert a cancer-promoting gain of function. We now report that cancer-associated mutant p53 can augment the induction of nuclear factor κB (NFκB) transcriptional activity in response to the cytokine tumor necrosis factor α (TNFα). Conversely, down-regulation of endogenous mutant p53 sensitizes cancer cells to the apoptotic effects of TNFα. Analysis of human head and neck tumors and lung tumors reveals a close correlation between the presence of abundant mutant p53 proteins and the constitutive activation of NFκB. Together, these findings suggest that p53 mutations may promote cancer progression by augmenting NFκB activation in the context of chronic inflammation. [Cancer Res 2007;67(6):2396–401]
Characterization of MicroRNA Expression Levels and Their Biological Correlates in Human Cancer Cell Lines
Authors: Gaur Arti , Jewell David A. , Liang Yu , Ridzon Dana , Moore Jason H. , Chen Caifu , Ambros Victor R. , Israel Mark A.
Published: March 2007

MicroRNAs are small noncoding RNAs that function by regulating target gene expression posttranscriptionally. They play a critical role in developmental and physiologic processes and are implicated in the pathogenesis of several human diseases including cancer. We examined the expression profiles of 241 human microRNAs in normal tissues and the NCI-60 panel of human tumor-derived cell lines. To quantify microRNA expression, we employed a highly sensitive technique that uses stem-loop primers for reverse transcription followed by real-time PCR. Most microRNAs were expressed at lower levels in tumor-derived cell lines compared with the corresponding normal tissue. Agglomerative hierarchical clustering analysis of microRNA expression revealed four groups among the NCI-60 cell lines consisting of hematologic, colon, central nervous system, and melanoma tumor–derived cell lines clustered in a manner that reflected their tissue of origin. We identified specific subsets of microRNAs that provide candidate molecular signatures characteristic of the tumor-derived cell lines belonging to these four clusters. We also identified specific microRNA expression patterns that correlated with the proliferation indices of the NCI-60 cell lines, and we developed evidence for the identification of specific microRNAs as candidate oncogenes and tumor suppressor genes in different tumor types. Our results provide evidence that microRNA expression patterns may mark specific biological characteristics of tumors and/or mediate biological activities important for the pathobiology of malignant tumors. These findings call attention to the potential of microRNAs to provide etiologic insights as well as to serve as both diagnostic markers and therapeutic targets for many different tumor types. [Cancer Res 2007;67(6):2456–68]