bluuebunny/crossref_metadata_2025 huggingface dataset:
Principles and Applications of Computer Graphics in Medicine
Authors: Vidal F.P. , Bello F. , Brodlie K.W. , John N.W. , Gould D. , Phillips R. , Avis N.J.
Published: March 2006

The medical domain provides excellent opportunities for the application of computer graphics, visualization and virtual environments, with the potential to help improve healthcare and bring benefits to patients. This survey paper provides a comprehensive overview of the state‐of‐the‐art in this exciting field. It has been written from the perspective of both computer scientists and practising clinicians and documents past and current successes together with the challenges that lie ahead. The article begins with a description of the software algorithms and techniques that allow visualization of and interaction with medical data. Example applications from research projects and commercially available products are listed, including educational tools; diagnostic aids; virtual endoscopy; planning aids; guidance aids; skills training; computer augmented reality and use of high performance computing. The final section of the paper summarizes the current issues and looks ahead to future developments.
Rendering Soft Shadows using Multilayered Shadow Fins
Authors: Cai Xiao‐Hua , Jia Yun‐Tao , Wang Xi , Hu Shi‐Min , Martin Ralph R.
Published: March 2006

Generating soft shadows in real time is difficult. Exact methods (such as ray tracing, and multiple light source simulation) are too slow, while approximate methods often overestimate the umbra regions. In this paper, we introduce a new algorithm based on the shadow map method to quickly and highly accurately render soft shadows produced by a light source. Our method builds inner and outer translucent fins on objects to represent the penumbra area inside and outside hard shadows, respectively. The fins are traced into multilayered light space maps to store illuminance adjustment to shadows. The viewing space illuminance buffer is then calculated using those maps. Finally, by blending illuminance and shading, a scene with highly accurate soft shadow effects is produced. Our method does not suffer from umbra overestimation. Physical relations between light, objects and shadows demonstrate the soundness of our approach.
Particle Oriented Collision Detection using Simplicial Coverings and Tetra‐Trees
Authors: Jiménez Juan José , Feito Francisco R. , Segura Rafael J. , Ogáyar Carlos J.
Published: March 2006

Collision detection (CD) among complex objects in motion is an open question because of its algorithmic complexity. In this paper, we present a CD algorithm between a particle and a complex rigid solid. In order to represent solids, we use a simplicial covering scheme by means of 3‐simplices. With this representation system, complex polyhedra and closed triangle meshes can be represented and used in CD with a particle. A particle can be represented by a point, where the real dimensions of the particle are not important. This CD algorithm has been extended for a particle represented by a sphere which in turn represents an approximation to the particle dimensions. In order to efficiently classify the particles and the simplices of the polyhedra covering, we use a new hierarchical data structure named tetra‐tree that decomposes the space into tetra‐cones. These algorithms also use bounding volumes and temporal and geometric coherence, as well as incremental calculations in order to determine the collision in an efficient and exact way. Because of the use of sign operations with signed volumes and barycentric coordinates, we conclude that operations carried out using this method are more robust and efficient than those used in classic algorithms.
A Weighted Error Metric and Optimization Method for Antialiasing Patterns
Authors: Laine S. , Aila T.
Published: March 2006

Displaying a synthetic image on a computer display requires determining the colors of individual pixels. To avoid aliasing, multiple samples of the image can be taken per pixel, after which the color of a pixel may be computed as a weighted sum of the samples. The positions and weights of the samples play a major role in the resulting image quality, especially in real‐time applications where usually only a handful of samples can be afforded per pixel. This paper presents a new error metric and an optimization method for antialiasing patterns used in image reconstruction. The metric is based on comparing the pattern against a given reference reconstruction filter in spatial domain, and it takes into account psychovisually measured angle‐specific acuities for sharp features.
A PBL Experience in the Teaching of Computer Graphics
Authors: Martí E. , Gil D. , Julià C.
Published: March 2006

Project‐Based Learning (PBL) is an educational strategy to improve student's learning capability that, in recent years, has had a progressive acceptance in undergraduate studies. This methodology is based on solving a problem or project in a student working group. In this way, PBL focuses on learning the necessary tools to correctly find a solution to given problems.

Since the learning initiative is transferred to the student, the PBL method promotes students own abilities. This allows a better assessment of the true workload that carries out the student in the subject. It follows that the methodology conforms to the guidelines of the Bologna document, which quantifies the student workload in a subject by means of the European credit transfer system (ECTS).

PBL is currently applied in undergraduate studies needing strong practical training such as medicine, nursing or law sciences. Although this is also the case in engineering studies, amazingly, few experiences have been reported. In this paper we propose to use PBL in the educational organization of the Computer Graphics subjects in the Computer Science degree.

Our PBL project focuses in the development of a C++ graphical environment based on the OpenGL libraries for visualization and handling of different graphical objects. The starting point is a basic skeleton that already includes lighting functions, perspective projection with mouse interaction to change the point of view and three predefined objects. Students have to complete this skeleton by adding their own functions to solve the project. A total number of 10 projects have been proposed and successfully solved. The exercises range from human face rendering to articulated objects, such as robot arms or puppets. In the present paper we extensively report the statement and educational objectives for two of the projects: solar system visualization and a chess game.

We report our earlier educational experience based on the standard classroom theoretical, problem and practice sessions and the reasons that motivated searching for other learning methods. We have mainly chosen PBL because it improves the student learning initiative. We have applied the PBL educational model since the beginning of the second semester. The student's feedback increases in his interest for the subject. We present a comparative study of the teachers' and students' workload between PBL and the classic teaching approach, which suggests that the workload increase in PBL is not as high as it seems.
Fast perceptual priming in the left and right hemispheres
Authors: KORSNES MARIA STYLIANOU , MAGNUSSEN SVEIN
Published: March 2006

Visual field differences in fast perceptual priming of possible and impossible object decisions were investigated in a go/no‐go task. Each participant (n= 74) was tested in two blocks of trials, each block containing 128 combinations of same‐field and cross‐field presentations of prime (blank) and target stimuli. The results indicate that fast perceptual priming of object decisions recruits processes that involve both cerebral hemispheres, independent of pre‐existing representation. The priming effect was larger for possible than for impossible objects, but fast perceptual priming of object‐decisions was demonstrated for both possible and impossible objects, in terms of both reaction times and accuracy. Left‐hemisphere specific priming for impossible stimuli may be due to a left hemisphere encoding advantage for impossible parts, consistent with a structural description account.
Do parents and adolescents differ in their perceptions of rearing styles? Analysis of the EMBU versions for parents and adolescents
Authors: ALUJA ANTON , BARRIO VICTORIA DEL , GARCÍA LUIS F.
Published: March 2006

In the present study, memories of rearing styles between parents, mother and father, and their son/daughters were explored through the EMBU versions for parents (EMBU‐P) and adolescents (EMBU‐A). Results show that parents differ in three of the four scales of the EMBU: Emotional Warmth, Control Attempts, and Favoring Subject. Also, mothers score higher on Emotional Warmth, and Control Attempts, but less on Favoring Subject. When parents and adolescents were compared in the common items to both versions, no substantial differences were found, except for the Favoring Subject scale. The sex of the adolescent seems not to play a relevant role in the observed differences. A revision of specialized literature suggested that differences in the fathers’ and mothers’ perceptions of their rearing styles could be related to differences in personality and marital satisfaction. These hypothetical relationships should be investigated in a parallel study.
Dynamics of verbal interaction between interviewer and child in interviews with alleged victims of child sexual abuse
Authors: KORKMAN JULIA , SANTTILA PEKKA , SANDNABBA N. KENNETH
Published: March 2006

A number (n= 27) of investigative interviews with children were analyzed with a view to explore the verbal dynamics between interviewer and child. Different types of interviewer utterances and child responses were defined, and the interrelationships between these were explored. The effectiveness of different interviewer utterances in eliciting information from children as well as the type of utterance the interviewer used to follow up an informative answer by the child were investigated. Option‐posing and suggestive utterances made up for more than 50% of interviewer utterances, the proportion of invitations being only 2%. Invitations and directive utterances were associated with an increase in informative responses by the child, the adverse being true for option‐posing and suggestive utterances. Interestingly, even after the child had provided an informative answer, interviewers continued to rely on focused and leading interviewing methods – in spite of a slight improvement in interviewing behavior.
Can music bring people together? Effects of shared musical preference on intergroup bias in adolescence
Authors: BAKAGIANNIS SOTIRIOS , TARRANT MARK
Published: March 2006

Recent research has successfully applied social identity theory to demonstrate how individuals use music as a basis for intergroup differentiation. The current study investigated how music might also be used to encourage the development of positive intergroup attitudes. Participants (N= 97) were allocated to one of two experimentally created social groups and then led to believe that the groups had similar or different musical preferences. They then evaluated each group and reported their perceptions concerning how they expected their own group to be evaluated by the other group. Participants who believed the groups had similar musical preferences reported more positive intergroup attitudes relative to a control group; they also expected to be evaluated more positively by members of the other group. However, positive intergroup perceptions were also reported by those who believed the two groups had different musical preferences. The implications of these findings for theory and practice are discussed.
On a Posterior Predictive Density Sample Size Criterion
Authors: NICOLERIS THEODOROS , WALKER STEPHEN G.
Published: March 2006

Abstract. Let Ω be a space of densities with respect to someσ‐finite measureμand letΠbe a prior distribution having support Ω with respect to some suitable topology. Conditional onf, letXn = (X1 ,…, Xn) be an independent and identically distributed sample of sizenfromf. This paper introduces a Bayesian non‐parametric criterion for sample size determination which is based on the integrated squared distance between posterior predictive densities. An expression for the sample size is obtained when the prior is a Dirichlet mixture of normal densities.
Estimation of the Association for Bivariate Interval‐censored Failure Time Data
Authors: SUN LIUQUAN , WANG LIANMING , SUN JIANGUO
Published: March 2006

Abstract. Multivariate failure time data frequently occur in medical studies and the dependence or association among survival variables is often of interest (Biometrics,51, 1995, 1384;Stat. Med.,18, 1999, 3101;Biometrika,87, 2000, 879;J. Roy. Statist. Soc. Ser. B,65, 2003, 257). We study the problem of estimating the association between two related survival variables when they follow a copula model and only bivariate interval‐censored failure time data are available. For the problem, a two‐stage estimation procedure is proposed and the asymptotic properties of the proposed estimator are established. Simulation studies are conducted to assess the finite sample properties of the presented estimate and the results suggest that the method works well for practical situations. An example from an acquired immunodeficiency syndrome clinical trial is discussed.
Satellite imagery activism: Sharpening the focus on tropical deforestation
Authors: Baker John C. , Williamson Ray A.
Published: March 2006

Since the first land remote sensing satellite was launched in the early 1970s, government agencies, private companies and research institutions have used satellite imagery data for a growing range of civil and commercial applications focused on natural resource management and exploitation, and environmental monitoring. The global diffusion of remote sensing expertize, along with growing public access to satellite images, has created conditions for improving levels of global transparency. One aspect of this global transparency is the advent of new users of imagery data – or ‘imagery activists’– including, among others, issue‐oriented nongovernmental organizations (NGOs), media groups, multinational organizations and academic researchers who now are able to access satellite imagery in order to draw domestic and international attention to particular public policy concerns. This paper broadly surveys the contemporary phenomenon of satellite imagery activism and outlines the main challenges facing imagery activists, particularly in relation to deforestation and other forest monitoring issues.
Tropical forest monitoring and remote sensing: A new era of transparency in forest governance?
Authors: Fuller Douglas O.
Published: March 2006

The extent of tropical deforestation is now being tracked by actors in the nongovernmental, academic, private and government sectors using several different sources of satellite imagery. This paper presents an overview of the satellite systems that can be used for operational forest monitoring in the tropics and examines some recent trends in their use. It also reviews various satellite‐based studies to map moist tropical forests and draws upon lessons learned from land cover mapping projects in several countries and regions. The case of Indonesia, examined as a nation undergoing rapid conversion of forest to other land uses, is contrasted with Brazil where satellite‐based deforestation monitoring is fully operational. In Indonesia, the paper argues, the creation of a national monitoring system for tropical forest conversion is needed to create a source of transparent, reliable information on forest cover and condition. Such a system is likely to succeed if based on multitemporal, moderate‐resolution optical data such as imagery provided by MODIS (Moderate Resolution Imaging Spectrometer). When MODIS images are complemented by radar and fine‐resolution imagery from sensors such as IKONOS and QuickBird, areas of abrupt change can be identified and the causes potentially discerned. Thus, satellite imagery at multiple temporal and spatial resolutions can effectively increase transparency in the forestry sector by revealing the rate and extent of deforestation on an annual basis and identifying potential areas of illegal logging.
Elucidating the murine brain transcriptional network in a segregating mouse population to identify core functional modules for obesity and diabetes
Authors: Lum Pek Yee , Chen Yanqing , Zhu Jun , Lamb John , Melmed Shlomo , Wang Susanna , Drake Tom A. , Lusis Aldons J. , Schadt Eric E.
Published: March 2006

Complex biological systems are best modeled as highly modular, fluid systems exhibiting a plasticity that allows them to adapt to a vast array of changing conditions. Here we highlight several novel network‐based approaches to elucidate genetic networks underlying complex traits. These integrative genomic approaches combine large‐scale genotypic and gene expression results in segregating mouse populations to reconstruct reliable genetic networks underlying complex traits such as disease or drug response. We apply these novel approaches to one of the most extensive surveys of gene expression studies ever undertaken in whole brain in a segregating mouse population. More than 23,000 genes were monitored in whole brain samples from more than 300 mice derived from an F2 intercross population and genotyped at over 1200 SNP markers uniformly spread over the entire genome. We explore the topological properties of the brain transcriptional network and highlight different approaches to inferring causal associations among genes by integrating genotypic and expression data. We demonstrate the utility of these approaches by identifying and experimentally validating brain gene expression traits predicted to respond to a strong expression quantitative trait locus (eQTL) for the pituitary tumor‐transforming 1 gene (Pttg1) that coincides with the physical location of this gene (a cis eQTL). We identify core functional modules making up the brain transcriptional network in mice that are coherent for core biological processes associated with metabolic disease traits including obesity and diabetes.
The norepinephrine transporter and its regulation
Authors: Mandela Prashant , Ordway Gregory A.
Published: March 2006

For many years, the norepinephrine transporter (NET) was considered a ‘static’ protein that contributed to the termination of the action of norepinephrine in the synapse of noradrenergic neurons. The concept that the NET is dynamically regulated, adjusting noradrenergic transmission by changing its function and/or expression, was considered initially in the mid 1980s. Since that time, a plethora of studies demonstrate that the NET is regulated by several intracellular and extracellular signaling molecules, and that phosphorylation of the NET is a major pathway regulating its cell surface expression and thereby its function. The NET is a target of action of a number of drugs that are used long‐term therapeutically or abused chronically. This has driven numerous investigations of how the NET and its function are regulated by long‐term exposure to drugs. While repeated exposure to many drugs has been shown to affect NET function and expression, the intracellular mechanisms for these effects remains elusive.
Role of phospholipase D2 in the agonist‐induced and constitutive endocytosis of G‐protein coupled receptors
Authors: Koch Thomas , Wu Dai‐Fei , Yang Li‐Quan , Brandenburg Lars‐Ove , Höllt Volker
Published: March 2006

We have recently shown that the μ‐opioid receptor [MOR1, also termed μ‐opioid peptide (MOP) receptor] is associated with the phospholipase D2 (PLD2), a phospholipid‐specific phosphodiesterase located in the plasma membrane. We further demonstrated that, in human embryonic kidney (HEK) 293 cells co‐expressing MOR1 and PLD2, treatment with (D‐Ala2, Me Phe4, Glyol5)enkephalin (DAMGO) led to an increase in PLD2 activity and an induction of receptor endocytosis, whereas morphine, which does not induce opioid receptor endocytosis, failed to activate PLD2. In contrast, a C‐terminal splice variant of the μ‐opioid receptor (MOR1D, also termed MOP1D) exhibited robust endocytosis in response to both DAMGO and morphine treatment. We report here that MOR1D also mediates an agonist‐independent (constitutive) PLD2‐activation facilitating agonist‐induced and constitutive receptor endocytosis. Inhibition of PLD2 activity by over‐expression of a dominant negative PLD2 (nPLD2) blocked the constitutive PLD2 activation and impaired the endocytosis of MOR1D receptors. Moreover, we provide evidence that the endocytotic trafficking of the δ‐opioid receptor [DOR, also termed δ‐opioid peptide (DOP) receptor] and cannabinoid receptor isoform 1 (CB1) is also mediated by a PLD2‐dependent pathway. These data indicate the generally important role for PLD2 in the regulation of agonist‐dependent and agonist‐independent G protein‐coupled receptor (GPCR) endocytosis.
Ethanol enhancement of cocaine‐ and amphetamine‐regulated transcript mRNA and peptide expression in the nucleus accumbens
Authors: Salinas Armando , Wilde Jennifer D. , Maldve Regina E.
Published: March 2006

Cocaine‐ and amphetamine‐regulated transcript (CART) is a peptide neurotransmitter that has been implicated in drug reward and reinforcement. CART mRNA and peptide expression are highly concentrated in several compartments of the mesolimbic reward pathway. Several lines of evidence suggest that CART peptides may contribute to rewarding behaviors and the addiction liability of psychostimulants; however, there are no reports of basic work concerning CART in relation to alcohol and mechanisms of alcohol dependence development. Therefore, in this study we investigated the response of CART transcript and peptide to acute ethanol administration in vivo. Rats were administered ethanol (1 g/kg or 3.5 g/kg, 1 h, ip) and CART expression was measured by RT‐PCR in the nucleus accumbens (NAcc). Ethanol (3.5 g/kg) increased CART transcription markedly. The interactions of dopamine on ethanol‐induced CART expression were further evaluated pharmacologically using D1 and D2/D3 receptor antagonists. Both SCH 23390 (0.25 mg/kg) or raclopride (0.2 mg/kg) pre‐treatment significantly suppressed ethanol‐enhancement of CART mRNA transcription. Confocal immunofluorescence microscopy revealed that CART peptide immunoreactivity was also enhanced in both the core and the shell of the NAcc by ethanol administration. These findings demonstrate that CART mRNA and peptide expression are responsive to acute ethanol administrated in vivo and suggests that CART peptides may be important in regulating the rewarding and reinforcing properties of ethanol.
Mu‐opioid receptors are involved in the tolerance to nicotine antinociception
Authors: Galeote Lola , Kieffer Brigitte L. , Maldonado Rafael , Berrendero Fernando
Published: March 2006

Several studies have shown the participation of the endogenous opioid system on the antinociceptive effects and addictive properties of nicotine. The aim of the present study was to explore the involvement of the mu‐opioid receptors in the development of tolerance to nicotine antinociception. Chronic treatment of C57BL/6 mice with nicotine (5 mg/kg s.c., three times daily during 12 days) resulted in tolerance to its antinociceptive responses in the tail‐immersion test. We investigated the possible existence of adaptive changes in the expression and/or functional activity of mu‐opioid receptors in these tolerant mice by using autoradiography of [3H]d‐Ala2‐MePhe4‐Gly‐ol5 enkephalin ([3H]DAMGO) binding and DAMGO‐stimulated guanosine [35S]5′‐(γ‐thio)‐triphosphate ([35S]GTPγS) binding. The density of mu‐opioid receptors in the spinal cord was not modified in nicotine‐tolerant mice, whereas a decrease was found in the caudate‐putamen, as well as in the core and the shell of the nucleus accumbens. However, the functional activity of these receptors was significantly increased in the spinal cord as a consequence of nicotine treatment. To further investigate the role of mu‐opioid receptors in the tolerance to nicotine‐induced antinociception, we evaluated this response in C57BL/6 mu‐opioid receptor knockout mice. Chronic nicotine treatment produced tolerance in both wild‐type and knockout animals, but tolerance developed faster in mice lacking mu‐opioid receptors. These results indicate that mu‐opioid receptors play an important role in the development of tolerance to nicotine antinociceptive effects.
Functional expression of the organic cation/carnitine transporter 2 in rat astrocytes
Authors: Inazu Masato , Takeda Hiroshi , Maehara Katsuyuki , Miyashita Kyoji , Tomoda Akio , Matsumiya Teruhiko
Published: March 2006

In this study, we sought to identify the transporters that mediate the uptake ofl‐carnitine and acetyl‐l‐carnitine in cultured rat cortical astrocytes.l‐[3H]carnitine and acetyl‐l‐[3H]carnitine uptake were both saturable, and mediated by a single Na+‐dependent transport system. Uptake of both was inhibited byl‐carnitine,d‐carnitine, acetyl‐l‐carnitine and various organic cations. Acylcarnitines (acetyl‐, butyryl‐, hexanoyl‐, octanoyl‐ and palmitoyl‐l‐carnitine) also interacted withl‐[3H]carnitine and acetyl‐l‐[3H]carnitine transport. 2‐Amino‐2‐norbornane carboxylic acid, a known inhibitor of amino acid transporter B0,+(ATB0,+), did not cause any significant inhibition. A highly significant correlation was found between the potencies of acylcarnitines in the inhibition ofl‐[3H]carnitine and acetyl‐l‐[3H]carnitine uptake and the acyl chain length of acylcarnitines. The expression of mRNA for organic cation/carnitine transporters (OCTNs), carnitine transporter 2 (CT2) and ATB0,+in astrocytes was investigated by reverse transcription (RT)–PCR. OCTN2 mRNA was expressed in astrocytes, whereas the expression of OCTN1, OCTN3 and CT2 mRNA could not be detected. ATB0,+mRNA was expressed at very low levels in astrocytes. Western blotting analysis indicated that anti‐OCTN2 polyclonal antibody recognized a band of 70 kDa in both kidney and astrocyte preparations. OCTN2 immunoreactivity was detected in rat astrocytes by immunocytochemical staining. Inhibition of OCTN2 expression by RNA interference significantly inhibitedl‐[3H]carnitine and acetyl‐l‐[3H]carnitine uptake into astrocytes. These results suggest that OCTN2 is functionally expressed in rat astrocytes, and is responsible forl‐carnitine and acetyl‐l‐carnitine uptake in these cells.
Neuroprotection against focal ischemic brain injury by the peroxisome proliferator‐activated receptor‐γ agonist rosiglitazone
Authors: Luo Yumin , Yin Wei , Signore Armando P. , Zhang Feng , Hong Zhen , Wang Suping , Graham Steven H. , Chen Jun
Published: March 2006

Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) is a nuclear membrane‐associated transcription factor that governs the expression of various inflammatory genes. PPAR‐γ agonists protect peripheral organs from ischemic injury. In the present study, we investigated whether the PPAR‐γ agonist rosiglitazone is neuroprotective against focal ischemic brain injury. C57/B6 mice underwent 1.5‐h middle cerebral artery occlusion, and received either vehicle or rosiglitazone treatment of 0.75, 1.5, 3, 6 or 12 mg/kg (n = 9 per group). Cerebral infarct volume, neurological function, expression of pro‐inflammatory proteins and neutrophil accumulation were assessed after ischemia and reperfusion. At 48 h after ischemia, infarct volume was significantly decreased with 3–12 mg/kg of rosiglitazone, with a time window of efficacy of 2 h after ischemia at the optimal dose (6 mg/kg). Neutrophil accumulation was significantly decreased in the brain parenchyma of rosiglitazone‐treated mice. Ischemia‐induced expression of several inflammatory cytokines and chemokines was markedly reduced in rosiglitazone‐treated brains, as determined using proteomic‐array analysis. Rosiglitazone treatment improved neurological function at 7 days after ischemia. Moreover, in cultured cortical primary microglia, rosiglitazone attenuated inflammatory responses by decreasing lipopolysaccharide‐induced release of tumor necrosis factor‐α, interleukin (IL)‐1β and IL‐6. These results suggest that the PPAR‐γ agonist rosiglitazone has neuroprotective properties that are at least partially mediated via anti‐inflammatory actions, and is thus a potential novel therapeutic agent for stroke.
Pharmacologically induced calcium oscillations protect neurons from increases in cytosolic calcium after trauma
Authors: Geddes‐Klein Donna M. , Serbest Gul , Mesfin Mahlet N. , Cohen Akiva S. , Meaney David F.
Published: March 2006

Increases in cytosolic calcium ([Ca2+]i) following mechanical injury are often considered a major contributing factor to the cellular sequelae in traumatic brain injury (TBI). However, very little is known on how developmental changes may affect the calcium signaling in mechanically injured neurons. One key feature in the developing brain that may directly impact its sensitivity to stretch is the reduced inhibition which results in spontaneous [Ca2+]i oscillations. In this study, we examined the mechanism of stretch‐induced [Ca2+]i transients in 18‐days in vitro (DIV) neurons exhibiting bicuculline‐induced [Ca2+]i oscillations. We used an in vitro model of mechanical trauma to apply a defined uniaxial strain to cultured cortical neurons and used increases in [Ca2+]i as a measure of the neuronal response to the stretch insult. We found that stretch‐induced increases in [Ca2+]i in 18‐DIV neurons were inhibited by pretreatment with either the NMDA receptor antagonist, APV [D(‐)‐2‐Amino‐5‐phosphonopentanoic acid], or by depolymerizing the actin cytoskeleton prior to stretch. Blocking synaptic NMDA receptors prior to stretch significantly attenuated most of the [Ca2+]i transient. In comparison, cultures with pharmacologically induced [Ca2+]i oscillations showed a substantially reduced [Ca2+]i peak after stretch. We provide evidence showing that a contributing factor to this mechanical desensitization from induced [Ca2+]i oscillations is the PKC‐mediated uncoupling of NMDA receptors (NMDARs) from spectrin, an actin‐associated protein, thereby rendering neurons insensitive to stretch. These results provide novel insights into how the [Ca2+]i response to stretch is initiated, and how reduced inhibition – a feature of the developing brain – may affect the sensitivity of the immature brain to trauma.
A one‐carbon modification of protein lysine associated with elevated oxidative stress in human substantia nigra
Authors: Floor Erik , Maples Anne M. , Rankin Carolyn A. , Yaganti Vamsee M. , Shank Sylvan S. , Nichols Grant S. , O'Laughlin Michael , Galeva Nadezhda A. , Williams Todd D.
Published: March 2006

We describe for the first time a naturally occurring lysine modification that is converted to methyllysine by reduction with sodium borohydride. This modification is ∼1.7 times as abundant in soluble proteins from human substantia nigra pars compacta as in proteins from other brain regions, possibly as a result of elevated oxidative stress in the nigra. Proteins from cultured PC12 cells exposed to oxidative stress conditions also contain elevated levels of this lysine modification. The abundance of the naturally occurring modification is roughly 0.08 nmoles/mg protein in either unstressed brain or PC12 cells. Modification levels remain stable in isolated proteins incubated for 2 h at 37°C in pH 7 buffer. We propose that the endogenous modification is the lysine Schiff base, ε‐N‐methylenelysine, and that lysine modifications may result from a reaction with formaldehyde in vivo. Rat brain contains ∼60 nmoles/g wet weight of formaldehyde, which probably includes both free and reversibly bound forms. Adding ∼35 µm HCHO to PC12 cell growth medium introduces methylenelysine modifications in cell proteins and impairs cell viability. The existence of this post‐translational modification suggests new mechanisms of oxidative stress that may contribute to tissue degeneration, including loss of nigral dopamine neurons during normal aging and in Parkinson's disease.
Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down's syndrome and related neurodegenerative diseases
Authors: Contestabile Andrea , Fila Tatiana , Bartesaghi Renata , Contestabile Antonio , Ciani Elisabetta
Published: March 2006

Ts65Dn mice, trisomic for a portion of chromosome 16 segmentally homologous to human chromosome 21, are an animal model for Down's syndrome and related neurodegenerative diseases, such as dementia of the Alzheimer type. In these mice, cognitive deficits and alterations in number of basal forebrain cholinergic neurons have been described. We have measured in Ts65Dn mice the catalytic activity of the cholinergic marker, choline acetyltransferase (ChAT), as well as the activity of the acetylcholine‐degrading enzyme acetylcholinesterase (AChE), in the hippocampus and in cortical targets of basal forebrain cholinergic neurons. In mice aged 10 months, ChAT activity was significantly higher in Ts65Dn mice, compared to 2N animals, in the hippocampus, olfactory bulb, olfactory cortex, pre‐frontal cortex, but not in other neocortical regions. At 19 months of age, on the other hand, no differences in ChAT activity were found. Thus, alterations of ChAT activity in these forebrain areas seem to recapitulate those recently described in patients scored as cases of mild cognitive impairment or mild Alzheimer's disease. Other neurochemical markers putatively associated with the disease progression, such as those implicating astrocytic hyperactivity and overproduction of amyloid precursor protein family, were preferentially found altered in some brain regions at the oldest age examined (19 months).
Reduction of iron‐regulated amyloid precursor protein and β‐amyloid peptide by (–)‐epigallocatechin‐3‐gallate in cell cultures: implications for iron chelation in Alzheimer's disease
Authors: Reznichenko L. , Amit T. , Zheng H. , Avramovich‐Tirosh Y. , Youdim M. B. H. , O. Weinreb  , Mandel S.
Published: March 2006

Brain iron dysregulation and its association with amyloid precursor protein (APP) plaque formation are implicated in Alzheimer's disease (AD) pathology and so iron chelation could be considered a rational therapeutic strategy for AD. Here we analyzed the effect of the main polyphenol constituent of green tea, (–)‐epigallocatechin‐3‐gallate (EGCG), which possesses metal‐chelating and radical‐scavenging properties, on the regulation of the iron metabolism‐related proteins APP and transferrin receptor (TfR). EGCG exhibited potent iron‐chelating activity comparable to that of the prototype iron chelator desferrioxamine, and dose dependently (1–10 µm) increased TfR protein and mRNA levels in human SH‐SY5Y neuroblastoma cells. Both the immature and full‐length cellular holo‐APP were significantly reduced by EGCG, as shown by two‐dimensional gel electrophoresis, without altering APP mRNA levels, suggesting a post‐transcriptional action. Indeed, EGCG suppressed the translation of a luciferase reporter gene fused to the APP mRNA 5′‐untranslated region, encompassing the APP iron‐responsive element. The finding that Fe2SO4 reversed the action of EGCG on APP and TfR proteins reinforces the likelihood that these effects are mediated through modulation of the intracellular iron pool. Furthermore, EGCG reduced toxic β‐amyloid peptide generation in Chinese hamster ovary cells overexpressing the APP ‘Swedish’ mutation. Thus, the natural non‐toxic brain‐permeable EGCG may provide a potential therapeutic approach for AD and other iron‐associated disorders.
XBP1 induces WFS1 through an endoplasmic reticulum stress response element‐like motif in SH‐SY5Y cells
Authors: Kakiuchi Chihiro , Ishiwata Mizuho , Hayashi Akiko , Kato Tadafumi
Published: March 2006

XBP1 is a key transcription factor in the endoplasmic reticulum (ER) stress response pathway. In a previous study, we suggested a possible link between XBP1 and bipolar disorder, but its role in neuronal cells has not yet been clarified. Here we examined the target genes of XBP1, using DNA microarray analysis in SH‐SY5Y cells transfected with an XBP1‐expressing vector. Among the genes up‐regulated by XBP1, the most significant p‐value was observed for WFS1, which is an ER stress response‐related gene. Examining the promoter region of WFS1, we found a conserved sequence (CGAGGCGCACCGTGATTGG) that is highly similar to the ER stress response element (ERSE). A promoter assay showed that this ERSE‐like motif is critical for the regulation of WFS1 by XBP1. An electrophoretic mobility shift assay suggested that XBP1 does not directly bind to this sequence. Our results demonstrate that WFS1 is one of the target genes of XBP1 in SH‐SY5Y cells.
TRF2 dysfunction elicits DNA damage responses associated with senescence in proliferating neural cells and differentiation of neurons
Authors: Zhang Peisu , Furukawa Katsutoshi , Opresko Patricia L. , Xu Xiangru , Bohr Vilhelm A. , Mattson Mark P.
Published: March 2006

Telomeres are specialized structures at the ends of chromosomes that consist of tandem repeats of the DNA sequence TTAGGG and several proteins that protect the DNA and regulate the plasticity of the telomeres. The telomere‐associated protein TRF2 (telomeric repeat binding factor 2) is critical for the control of telomere structure and function; TRF2 dysfunction results in the exposure of the telomere ends and activation of ATM (ataxia telangiectasin mutated)‐mediated DNA damage response. Recent findings suggest that telomere attrition can cause senescence or apoptosis of mitotic cells, but the function of telomeres in differentiated neurons is unknown. Here, we examined the impact of telomere dysfunction via TRF2 inhibition in neurons (primary embryonic hippocampal neurons) and mitotic neural cells (astrocytes and neuroblastoma cells). We demonstrate that telomere dysfunction induced by adenovirus‐mediated expression of dominant‐negative TRF2 (DN‐TRF2) triggers a DNA damage response involving the formation of nuclear foci containing phosphorylated histone H2AX and activated ATM in each cell type. In mitotic neural cells DN‐TRF2 induced activation of both p53 and p21 and senescence (as indicated by an up‐regulation of β‐galactosidase). In contrast, in neurons DN‐TRF2 increased p21, but neither p53 nor β‐galactosidase was induced. In addition, TRF2 inhibition enhanced the morphological, molecular and biophysical differentiation of hippocampal neurons. These findings demonstrate divergent molecular and physiological responses to telomere dysfunction in mitotic neural cells and neurons, indicate a role for TRF2 in regulating neuronal differentiation, and suggest a potential therapeutic application of inhibition of TRF2 function in the treatment of neural tumors.
Notch and NGF/p75NTR control dendrite morphology and the balance of excitatory/inhibitory synaptic input to hippocampal neurones through Neurogenin 3
Authors: Salama‐Cohen Patricia , Arévalo María‐Ángeles , Grantyn Rosemarie , Rodríguez‐Tébar Alfredo
Published: March 2006

We have previously shown that dendrite morphology of cultured hippocampal neurones is controlled by Notch receptor activation or binding of nerve growth factor (NGF) to its low affinity receptor p75NTR, i.e. processes that up‐regulate the expression of the Homologue of enhancer of split 1 and 5. Thus, the increased expression of these genes decreases the number of dendrites, whereas abrogation of Homologue of enhancer of split 1/5 activity stimulates the outgrowth of new dendrites. Here, we show that Neurogenin 3 is a proneural gene that is negatively regulated by Homologue of enhancer of split 1/5. It also influences dendrite morphology. Hence, a deficit of Notch or NGF/p75NTRactivation can lead to the production of high levels of Neurogenin 3, which stimulates the outgrowth of new dendrites. Conversely, activation of either Notch or p75NTR depressed Neurogenin 3 expression, which not only decreased the number of dendrites but also favoured inhibitory (GABAergic) synaptogenesis, thereby diminishing the ratios of excitatory/inhibitory inputs. NGF also augmented the levels of mRNA encoding the vesicular inhibitory amino acid transporter, but it did not affect the fraction of GAD65/67‐positive neurones. Conversely, overexpression of Neurogenin 3 largely reduced the number of inhibitory synaptic contacts and, consequently, produced a strong increase in the ratios of excitatory/inhibitory synaptic terminals. Our results reveal a hitherto unknown contribution of NGF/p75NTR to dendritic and synaptic plasticity through Neurogenin 3 signalling.
d‐Aspartate as a putative cell–cell signaling molecule in the Aplysia californica central nervous system
Authors: Miao Hai , Rubakhin Stanislav S. , Scanlan Cory R. , Wang Liping , Sweedler Jonathan V.
Published: March 2006

The content, synthesis and transport of d‐aspartate (d‐Asp) in the CNS of Aplysia californica is investigated using capillary electrophoresis (CE) with both laser‐induced fluorescence and radionuclide detection. Millimolar concentrations of d‐Asp are found in various regions of the CNS. In the cerebral ganglion, three adjacent neuronal clusters have reproducibly different d‐Asp levels; for example, in the F‐ and C‐clusters, up to 85% of the free Asp is present in the d‐form. Heterogeneous distribution of d‐Asp is also found in the individual identified neurons tested, including the optical ganglion top‐layer neurons, metacerebral cells, R2 neurons, and F‐, C‐ and G‐cluster neurons. The F‐cluster neurons have the highest percentage of d‐Asp (∼58% of the total Asp), whereas the lowest value of ∼8% is found in R2 neurons. In pulse‐chase experiments with radiolabeled d‐Asp, followed by CE with radionuclide detection, the synthesis of d‐Asp from l‐aspartate (l‐Asp) is confirmed. Is d‐Asp in the soma, or is it transported to distantly located release sites? d‐Asp is clearly detected in the major nerves of A. californica, including the pleuroabdominal and cerebrobuccal connectives and the anterior tentacular nerves, suggesting it is transported long distances. In addition, both d‐Asp and l‐Asp are transported in the pleuroabdominal connectives in a colchicine‐dependent manner, whereas several other amino acids are not. Finally, d‐Asp produces electrophysiological effects similar to those induced by l‐Asp. These data are consistent with an active role for d‐Asp in cell‐to‐cell communication.
Abundance of triacylglycerols in ganglia and their depletion in diabetic mice: implications for the role of altered triacylglycerols in diabetic neuropathy
Authors: Cheng Hua , Guan Shaoping , Han Xianlin
Published: March 2006

Herein, we report the first study on the mass distribution and molecular species composition of abundant triacylglycerols (TAG) in ganglia. This study demonstrates five novel findings. First, unanticipated high levels of TAG were present in all examined ganglia from multiple species (e.g. mouse, rat and rabbit). Second, ganglial TAG mass content is location‐dependent. Third, the TAG mass levels in ganglia are species‐specific. Fourth, dorsal root ganglial TAG mass levels in streptozotocin‐induced diabetic mice are dramatically depleted relative to those found in untreated control mice. Fifth, mouse ganglial TAG mass levels decrease with age although molecular species composition is not changed. Collectively, these results indicate that TAG is an important component of ganglia and may potentially contribute to pathological alterations in peripheral neuronal function in diabetic neuropathy.
Toxicity and biodistribution of an iodine‐131‐radiolabelled tumour necrosis‐targeting antibody in non‐tumour‐bearing domestic felines
Authors: Van Walleghen D. M. , Parseghian M. H.
Published: March 2006

The potential of human immunotherapeutics now revolutionizing modern cancer therapy has yet to make an impact in veterinary medicine, mainly due to the evolutionary differences between human and non‐human cell surface antigens which bar the efficacy for many antibodies targeting human antigens. Here, we explore the possible use of an iodine‐131 (I‐131)‐radiolabelled chimericTNT‐1/B antibody, Cotara, being tested in humans, which targets a highly conserved structure present in all solid tumours. The goal was to document the possible toxic side‐effects, retention, excretion and biodistribution of Cotara in non‐tumour‐bearing felines. The study was conducted with six lab animal domestic shorthaired felines. Two felines were randomly placed into three dose groups: 1.5, 2.0, and 3.0 mCi kg−1(0.68, 0.9 and 1.36 mCi lb−1); these doses were administered by a single IV injection. Thyroid blockade with potassium iodide (KI) was administered orally once daily. Over the 90‐day study, haematologic test results, serum chemistry, thyroid function, food intake and morbidity were recorded. Drug distribution was ascertained through nuclear scintigraphy. Four of the six subjects had decreased appetite (Grade 1) that started on day 4 and then resolved by day 10. Two subjects exhibited intermittent days of anorexia (Grade 2) from day 5 to day 13. Both subjects with Grade 2 anorexia were sacrificed and necropsied once each exhibited two consecutive days of signs. Vomiting (Grade 2) occurred in 3 subjects from day 4 to day 13. Three subjects had moderate regenerative anaemia (Grade 2), whereas two developed leucocytosis. Overall, a single intravenous dose of Cotara resulted in moderate toxicity, with subjects exhibiting transitory signs of anorexia and vomiting without laboratory evidence of organ pathology. Each subject received a once daily oral dose of KI (33 mg) that was found to be safe and effective in the prevention of radiation damage to the thyroid gland over the study period. With a moderate toxicity profile, Cotara may hold unique promise by delivering I‐131 directly into solid tumours of various types in felines.
Extragenital transmissible venereal tumour associated with circulating neoplastic cells in an immunologically compromised dog
Authors: Albanese F. , Salerni F. L. , Giordano S. , Marconato L.
Published: March 2006

An adult male intact boxer was presented because of diffuse cutaneous nodules. Fine‐needle aspirate revealed transmissible venereal tumour (TVT) cells. Neoplastic cells were also observed in the peripheral blood. Associated simultaneous diseases included leishmaniosis, demodicosis, papillomatosis and coccidiosis. Immunosuppression may have aggravated disease and triggered widespread metastases. The dog was hospitalized and administered oral amoxicillin/clavulanate, subcutaneous meglumine antimonite to treat leishmaniosis and oral chlortetracycline to treat coccidiosis. Intravenous injection of vincristine at weekly interval was used to treat TVT. A rapid regression of cutaneous nodules was noted; however, intractable diarrhoea developed, eventually leading to death after 18 days. This is the first report describing an unusual case of extragenital TVT associated with circulating neoplastic cells in an immunosuppressed dog presenting with multiple cutaneous nodules.
Surgical cytoreduction for the treatment of non‐lymphoid vertebral and spinal cord neoplasms in cats: retrospective evaluation of 26 cases (1990–2005)
Authors: Rossmeisl J. H. , Lanz O. I. , Waldron D. R. , Shires P. K. , Zimmerman K. L. , Sego L. H.
Published: March 2006

Medical records of 26 cats with non‐lymphoid vertebral and spinal cord neoplasms treated surgically were reviewed to determine outcome and prognostic factors for survival. Of the factors examined, only tumour phenotype was significantly associated with survival. Osteosarcoma (3/26 cats) and meningioma (16/26 cats) were the most common malignant and benign tumours, respectively. The median survival time for cats with malignant neoplasms was 110.5 days, compared with 518 days for cats with benign tumours. Cytoreductive surgery resulted in clinical improvement in 25/26 cats, but local treatment failure occurred in 10/26 cats. Overall, 19/26 cats died of confirmed (12/19) or suspected (7/19) tumour‐related causes, including all eight cats with malignant neoplasms. Results suggest that contemporary neurosurgical techniques commonly result in incomplete excision of feline non‐lymphoid vertebral and spinal cord tumours but are efficacious at palliation of clinical signs of spinal cord dysfunction.