Handheld-assisted field data collection for occupational risk assessment.

A computerized handheld procedure is presented in this paper. It is intended as a database complementary tool, to enhance prospective risk analysis in the field of occupational health. The Pendragon forms software (version 3.2) has been used to implement acquisition procedures on Personal Digital Assistants (PDAs) and to transfer data to a computer in an MS-Access format. The data acquisition strategy proposed relies on the risk assessment method practiced at the Institute of Occupational Health Sciences (IST). It involves the use of a systematic hazard list and semi-quantitative risk assessment scales. A set of 7 modular forms has been developed to cover the basic need of field audits. Despite the minor drawbacks observed, the results obtained so far show that handhelds are adequate to support field risk assessment and follow-up activities. Further improvements must still be made in order to increase the tool effectiveness and field adequacy.

The category 'natural' in the discourse of couples who used medically assisted procreation

As a constantly evolving set of complex biotechnologies, medically assisted procreation (MAP) jeopardises a category that seems to be taken for granted: that of 'natural'. What is 'natural' or not when MAP is used to procreate? What are the boundaries between a 'natural' and a 'non-natural' fertilisation? Drawing upon a dialogical approach to language and cognition, our study examined the semantic field of the category 'natural' as expressed in interviews between a psychiatrist and seven couples who resorted to MAP and had to decide whether to keep their frozen pre-embryonic cells (zygotes) for further procreation or to allow them be destroyed. We examined how these couples evoked the category 'natural' and showed that in their argumentation, the category 'natural' encompassed a wide variety of phenomena, which shifted the boundaries between the 'natural' and 'non-natural'. In so doing, the couples 'renaturalised' MAP, normalized it, moved the boundaries between what is legitimate or not, and showed their accountability. Hence, reference to the category 'natural' seemed to act both as an argumentative and a psychological resource in the elaboration of the person's experience in resorting to MAP.

Dissociation of allocentric and egocentric orientation: Effect on hippocampal place cells and place navigation

Navigation by means of cognitive maps appears to require the hippocampus; hippocampal place cells (PCs) appear to store spatial memories because their discharge is confined to cell-specific places called firing fields (FFs). Experiments with rats manipulated idiothetic and landmark-related information to understand the relationship between PC activity and spatial rotation. Rotating a circular arena in the caused a discrepancy between these cuse. This discrepancy caused most FFs to disappear in both the arena and room reference frames. However, FFs persisted in the rotating arena frame when the discrepancy was reduced by darkness or by a card in the arena. The discrepancy was increased by "field clamping" the rat in a room-defined FF location by rotations that countered its locomotion. Most FFs disspared and reappeared an hour or more after the clamp. Place-avoidance experiments showed that navigation uses independent idiothetic and exteroceptive memories. Rats learned to avoid the unmarked footshock region within a circular arena. When acquired on the stable arena in the light, the location of the punishment was learned by using both room and idiothetic cues; extinction in the dark transferred to the following session in the light. If, however, extinction occured during rotation, only the arena-frame avoidance was extinguished in darkness; the room-defined location was avoided when the light were turned back on. Idiothetic memory of room-defined avoidance was not formed during rotation in light; regardless of rotation with a randomly dispersed pellet. The resulting behaviour alternated between random pellet searching and target-directed navigation, making it possible to examine PC correlates of these two classes of spatial behaviour. The independence of idiothetic and exteroceptive spatial memories and the disruption of PC firing during rotation suggest that PCs may not be necessary for spatial cognition; this idea can be tested by recording during place-avoidance and preference tasks.

Dense deformation field estimation for atlas-based segmentation of pathological MR brain images.

Atlas registration is a recognized paradigm for the automatic segmentation of normal MR brain images. Unfortunately, atlas-based segmentation has been of limited use in presence of large space-occupying lesions. In fact, brain deformations induced by such lesions are added to normal anatomical variability and they may dramatically shift and deform anatomically or functionally important brain structures. In this work, we chose to focus on the problem of inter-subject registration of MR images with large tumors, inducing a significant shift of surrounding anatomical structures. First, a brief survey of the existing methods that have been proposed to deal with this problem is presented. This introduces the discussion about the requirements and desirable properties that we consider necessary to be fulfilled by a registration method in this context: To have a dense and smooth deformation field and a model of lesion growth, to model different deformability for some structures, to introduce more prior knowledge, and to use voxel-based features with a similarity measure robust to intensity differences. In a second part of this work, we propose a new approach that overcomes some of the main limitations of the existing techniques while complying with most of the desired requirements above. Our algorithm combines the mathematical framework for computing a variational flow proposed by Hermosillo et al. [G. Hermosillo, C. Chefd'Hotel, O. Faugeras, A variational approach to multi-modal image matching, Tech. Rep., INRIA (February 2001).] with the radial lesion growth pattern presented by Bach et al. [M. Bach Cuadra, C. Pollo, A. Bardera, O. Cuisenaire, J.-G. Villemure, J.-Ph. Thiran, Atlas-based segmentation of pathological MR brain images using a model of lesion growth, IEEE Trans. Med. Imag. 23 (10) (2004) 1301-1314.]. Results on patients with a meningioma are visually assessed and compared to those obtained with the most similar method from the state-of-the-art.

Renal arteries: navigator-gated balanced fast field-echo projection MR angiography with aortic spin labeling: initial experience.

A cardiac-triggered free-breathing three-dimensional balanced fast field-echo projection magnetic resonance (MR) angiographic sequence with a two-dimensional pencil-beam aortic labeling pulse was developed for the renal arteries. For data acquisition during free breathing in eight healthy adults and seven consecutive patients with renal artery disease, real-time navigator technology was implemented. This technique allows high-spatial-resolution and high-contrast renal MR angiography and visualization of renal artery stenosis without exogenous contrast agent or breath hold. Initial promising results warrant larger clinical studies.

Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions

A series of 4 experiments examined the performance of rats with retrohippocampal lesions on a spatial water-maze task. The animals were trained to find and escape onto a hidden platform after swimming in a large pool of opaque water. The platform was invisible and could not be located using olfactory cues. Successful escape performance required the rats to develop strategies of approaching the correct location with reference solely to distal extramaze cues. The lesions encompassed the entire rostro-caudal extent of the lateral and medial entorhinal cortex, and included parts of the pre- and para-subiculum, angular bundle and subiculum. Groups ECR 1 and 2 sustained only partial damage of the subiculum, while Group ECR+S sustained extensive damage. These groups were compared with sham-lesion and unoperated control groups. In Expt 1A, a profound deficit in spatial localisation was found in groups ECR 1 and ECR+S, the rats receiving all training postoperatively. In Expt 1B, these two groups showed hyperactivity in an open-field. In Expt 2, extensive preoperative training caused a transitory saving in performance of the spatial task by group ECR 2, but comparisons with the groups of Expt 1A revealed no sustained improvement, except on one measure of performance in a post-training transfer test. All rats were then given (Expt 3) training on a cueing procedure using a visible platform. The spatial deficit disappeared but, on returning to the normal hidden platform procedure, it reappeared. Nevertheless, a final transfer test, during which the platform was removed from the apparatus, revealed a dissociation between two independent measures of performance: the rats with ECR lesions failed to search for the hidden platform but repeatedly crossed its correct location accurately during traverses of the entire pool. This partial recovery of performance was not (Expt 4) associated with any ability to discriminate between two locations in the pool. The apparently selective recovery of aspects of spatial memory is discussed in relation to O'Keefe and Nadel's (1978) spatial mapping theory of hippocampal function. We propose a modification of the theory in terms of a dissociation between procedural and declarative subcomponents of spatial memory. The declarative component is a flexible access system in which information is stored in a form independent of action. It is permanently lost after the lesion. The procedural component is "unmasked" by the retrohippocampal lesion giving rise to the partial recovery of spatial localisation performance.

PulseCath iVAC 3LTM hemodynamic performance for simple assisted flow.

The PulseCath iVAC 3L? left ventricular assist device is an option to treat transitory left heart failure or dysfunction post-cardiac surgery. Assisted blood flow should reach up to 3 l/min. In the present in vitro model exact pump flow, depending on various frequencies and afterload was examined. Optimal flow was achieved with inflation/deflation frequencies of about 70-80/min. The maximal flow rate was achieved at about 2.5 l/min with a minimal afterload of 22 mmHg. Handling of the device was easy due to the connection to a standard intra-aortic balloon pump console. With increasing afterload (up to a simulated mean systemic pressure of 66 mmHg) flow rate and cardiac support are in some extent limited.

Non-assisted versus neuro-navigated and XperCT-guided external ventricular catheter placement: a comparative cadaver study.

BACKGROUND AND PURPOSE: Accurate placement of an external ventricular drain (EVD) for the treatment of hydrocephalus is of paramount importance for its functionality and in order to minimize morbidity and complications. The aim of this study was to compare two different drain insertion assistance tools with the traditional free-hand anatomical landmark method, and to measure efficacy, safety and precision. METHODS: Ten cadaver heads were prepared by opening large bone windows centered on Kocher's points on both sides. Nineteen physicians, divided in two groups (trainees and board certified neurosurgeons) performed EVD insertions. The target for the ventricular drain tip was the ipsilateral foramen of Monro. Each participant inserted the external ventricular catheter in three different ways: 1) free-hand by anatomical landmarks, 2) neuronavigation-assisted (NN), and 3) XperCT-guided (XCT). The number of ventricular hits and dangerous trajectories; time to proceed; radiation exposure of patients and physicians; distance of the catheter tip to target and size of deviations projected in the orthogonal plans were measured and compared. RESULTS: Insertion using XCT increased the probability of ventricular puncture from 69.2 to 90.2 % (p = 0.02). Non-assisted placements were significantly less precise (catheter tip to target distance 14.3 ± 7.4 mm versus 9.6 ± 7.2 mm, p = 0.0003). The insertion time to proceed increased from 3.04 ± 2.06 min. to 7.3 ± 3.6 min. (p < 0.001). The X-ray exposure for XCT was 32.23 mSv, but could be reduced to 13.9 mSv if patients were initially imaged in the hybrid-operating suite. No supplementary radiation exposure is needed for NN if patients are imaged according to a navigation protocol initially. CONCLUSION: This ex vivo study demonstrates a significantly improved accuracy and safety using either NN or XCT-assisted methods. Therefore, efforts should be undertaken to implement these new technologies into daily clinical practice. However, the accuracy versus urgency of an EVD placement has to be balanced, as the image-guided insertion technique will implicate a longer preparation time due to a specific image acquisition and trajectory planning.

Results of computer assisted navigation in Total Knee Arthroplasty (TKA): comparison with the conventional method

The aim of this retrospective study was to compare the clinical and radiographic results after TKA (PFC, DePuy), performed either by computer assisted navigation (CAS, Brainlab, Johnson&Johnson) or by conventional means. Material and methods: Between May and December 2006 we reviewed 36 conventional TKA performed between 2002 and 2003 (group A) and 37 navigated TKA performed between 2005 and 2006 (group B) by the same experienced surgeon. The mean age in group A was 74 years (range 62-90) and 73 (range 58-85) in group B with a similar age distribution. The preoperative mechanical axes in group A ranged from -13° varus to +13° valgus (mean absolute deviation 6.83°, SD 3.86), in group B from -13° to +16° (mean absolute deviation 5.35, SD 4.29). Patients with a previous tibial osteotomy or revision arthroplasty were excluded from the study. Examination was done by an experienced orthopedic resident independent of the surgeon. All patients had pre- and postoperative long standing radiographs. The IKSS and the WOMAC were utilized to determine the clinical outcome. Patient's degree of satisfaction was assessed on a visual analogous scale (VAS). Results: 32 of the 37 navigated TKAs (86,5%) showed a postoperative mechanical axis within the limits of 3 degrees of valgus or varus deviation compared to only 24 (66%) of the 36 standard TKAs. This difference was significant (p = 0.045). The mean absolute deviation from neutral axis was 3.00° (range -5° to +9°, SD: 1.75) in group A in comparison to 1.54° (range -5° to +4°, SD: 1.41) in group B with a highly significant difference (p = 0.000). Furthermore, both groups showed a significant postoperative improvement of their mean IKSS-values (group A: 89 preoperative to 169 postoperative, group B 88 to 176) without a significant difference between the two groups. Neither the WOMAC nor the patient's degree of satisfaction - as assessed by VAS - showed significant differences. Operation time was significantly higher in group B (mean 119.9 min.) than in group A (mean 99.6 min., p <0.000). Conclusion: Our study showed consistent significant improvement of postoperative frontal alignment in TKA by computer assisted navigation (CAS) compared to standard methods, even in the hands of a surgeon well experienced in standard TKA implantation. However, the follow-up time of this study was not long enough to judge differences in clinical outcome. Thus, the relevance of computer navigation for clinical outcome and survival of TKA remains to be proved in long term studies to justify the longer operation time. References 1 Stulberg SD. Clin Orth Rel Res. 2003;(416):177-84. 2 Chauhan SK. JBJS Br. 2004;86(3):372-7. 3 Bäthis H, et al. Orthopäde. 2006;35(10):1056-65.

Performance of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of bacterial strains routinely isolated in a clinical microbiology laboratory.

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has recently been introduced in diagnostic microbiology laboratories for the identification of bacterial and yeast strains isolated from clinical samples. In the present study, we prospectively compared MALDI-TOF MS to the conventional phenotypic method for the identification of routine isolates. Colonies were analyzed by MALDI-TOF MS either by direct deposition on the target plate or after a formic acid-acetonitrile extraction step if no valid result was initially obtained. Among 1,371 isolates identified by conventional methods, 1,278 (93.2%) were putatively identified to the species level by MALDI-TOF MS and 73 (5.3%) were identified to the genus level, but no reliable identification was obtained for 20 (1.5%). Among the 1,278 isolates identified to the species level by MALDI-TOF MS, 63 (4.9%) discordant results were initially identified. Most discordant results (42/63) were due to systematic database-related taxonomical differences, 14 were explained by poor discrimination of the MALDI-TOF MS spectra obtained, and 7 were due to errors in the initial conventional identification. An extraction step was required to obtain a valid MALDI-TOF MS identification for 25.6% of the 1,278 valid isolates. In conclusion, our results show that MALDI-TOF MS is a fast and reliable technique which has the potential to replace conventional phenotypic identification for most bacterial strains routinely isolated in clinical microbiology laboratories.

Perinatal choline supplementation reveals a dissociation between two types of spatial strategies.

Choline supplementation improving memory functions in rodents is assumed to increase the synthesis and release of acetylcholine in the brain. We have found that a combined pre- and postnatal supplementation results in long-lasting facilitation of spatial memory in juvenile rats when training was conducted in presence of a local salient cue. The present work was aimed at analysing the effects of peri- and postnatal choline supplementation on spatial abilities of naive adult rats. Rats given a perinatal choline supplementation were trained in various cued procedures of the Morris navigation task when aged 5 months. The treatment had a specific effect of reducing the escape latency of the rats when the platform was at a fixed position in space and surrounded by a suspended cue. This effect was associated with an increased spatial bias when the cue and platform were removed. In this condition, the control rats showed impaired spatial discrimination following the removal of the target cue, most likely due to an overshadowing of the distant environmental cues. This impairment was not observed in the treated rats. Further training with the suspended cue at unpredictable places in the pool revealed longer escape latencies in the control than in the treated rats suggesting that this procedure induced a selective perturbation of the normal but not of the treated rats. A special probe trial with the cue at an irrelevant position and no escape platform revealed a significant bias of the control rats toward the cue and of the treated rats toward the uncued spatial escape position. This behavioural dissociation suggests that a salient cue associated with the target induces an alternative "non spatial" guidance strategy in normal rats, with the risk of overshadowing of the more distant spatial cues. In this condition, the choline supplementation facilities a spatial reliance on the cue, that is an overall facilitation of learning a set of spatial relations between several visual cues. As a consequence, the improved escape in presence of the cue is associated with a stronger memory of the spatial position following disappearance of the cue. This and previous observations suggest that a specific spatial attention process relies on the buffering of highly salient visual cues.to facilitate integration of their relative position in the environment.

Auditory spatial deficits following hemispheric lesions : dissociation of explicit and implicit processing

Les déficits auditifs spatiaux se produisent fréquemment après une lésion hémisphérique ; un précédent case report suggérait que la capacité explicite à reconnaître des positions sonores, comme dans la localisation des sons, peut être atteinte alors que l'utilisation implicite d'indices sonores pour la reconnaissance d'objets sonores dans un environnement bruyant reste préservée. En testant systématiquement des patients avec lésion hémisphérique inaugurale, nous avons montré que (1) l'utilisation explicite et/ou implicite des indices sonores peut être perturbée ; (2) la dissociation entre l'atteinte de l'utilisation explicite des indices sonores versus une préservation de l'utilisation implicite de ces indices est assez fréquente ; et (3) différents types de déficits dans la localisation des sons peuvent être associés avec une utilisation implicite préservée de ces indices sonores. Conceptuellement, la dissociation entre l'utilisation explicite et implicite de ces indices sonores peut illustrer la dichotomie des deux voies du système auditif. Nos résultats parlent en faveur d'une évaluation systématique des fonctions auditives spatiales dans un contexte clinique, surtout quand l'adaptation à un environnement sonore est en jeu. De plus, des études systématiques sont nécessaires afin de mettre en lien les troubles de l'utilisation explicite versus implicite de ces indices sonores avec les difficultés à effectuer les activités de la vie quotidienne, afin d'élaborer des stratégies de réhabilitation appropriées et afin de s'assurer jusqu'à quel point l'utilisation explicite et implicite des indices spatiaux peut être rééduquée à la suite d'un dommage cérébral.

AFT3 as a new therapeutic target for skin field cancerization in antagonism with compromised Notch/CSL signaling

Les interactions épithélio-mésenchymateuses jouent un rôle important dans le contrôle du développement normal de la peau, son homéostasie et sa tumorigenèse. Les fibroblastes dermiques (DFs) représentent la catégorie cellulaire la plus abondante dans le stroma et leur rôle est de plus en plus considéré. En ce qui concerne particulièrement la tumorigenèse, des facteurs diffusibles produits par les fibroblastes entourant les tumeurs épithéliales, appelés 'fibroblastes associés au cancer (CAF)', interagissent au niveau de l'inflammation impliquée directement ou indirectement dans la signalisation paracrine, entre le stroma et les cellules épiéliales cancéreuses. Le risque de cancer de la peau augmente de façon exponentielle avec l'âge. Comme un lien probable entre les deux, la sénescence des fibroblastes résulte de la production du sécrétome favorisant la sénescence (SMS), un groupe de facteurs diffusibles induisant une stimulation paracrine de la croissance, l'inflammation et le remodelage de la matrice. De façon fort intéressante, l'induction de ces gènes est aussi une caractéristique des CAFs. Cependant, le lien entre les deux événements cellulaires sénescence et activation des CAFs reste en grande partie inexploré. L'ATF3 (Activating Transcription Factor 3) est un facteur de transcription induit en réponse au stress, dont les fonctions sont hautement spécifiques du type cellulaire. Bien qu'il ait été découvert dans notre laboratoire en tant que promoteur de tumeurs dans les kératinocytes, ses fonctions biologique et biochimique dans le derme n'ont pas encore été étudiées. Récemment, nous avons constaté que, chez la souris, l'abrogation de la voie de signalisation de Notch/CSL dans les DFs, induisait la formation de tumeurs kératinocytaires multifocales. Ces dernières proviennent de la cancérisation en domaine, un phénomène associé à une atrophie du stroma, des altérations de la matrice et de l'inflammation. D'autres études ont montré que CSL agissait comme un régulateur négatif de gènes impliqués dans sénescence des DFs et dans l'activation des CAFs. Ici, nous montrons que la suppression ou l'atténuation de l'expression de ATF3 dans les DFs induit la sénescence et l'expression des gènes liés aux CAFs, de façon similaire à celle déclenchée par la perte de CSL, tandis que la surexpression de ATF3 supprime ces changements. Nous émettons l'hypothèse que ATF3 joue un rôle suppresseur dans l'activation des CAFs et dans la progression des tumeurs kératinocytaires, en surmontant les conséquences de l'abrogation de la voie de signalisation Notch/CSL. En concordance avec cette hypothèse, nous avons constaté que la perte de ATF3 dans les DFs favorisait la tumorigénicité des kératinocytes via le contrôle négatif de cytokines, des enzymes de la matrice de remodelage et de protéines associées au cancer, peut-être par liaison directe des effecteurs de la voie Notch/CSL : IL6 et les gènes Hes. Enfin, dans les échantillons cliniques humains, le stroma sous-jacent aux lésions précancéreuses de kératoses actiniques montre une diminution significative de l'expression de ATF3 par rapport au stroma jouxtant la peau normale. La restauration de l'expression de ATF3 pourrait être utilisée comme un outil thérapeutique en recherche translationnelle pour prévenir ou réprimer le processus de cancérisation en domaine. - Epithelial-mesenchymal interactions play an important role in control of normal skin development, homeostasis and tumorigenesis. The role of dermal fibroblasts (DFs) as the most abundant cell type in stroma is increasingly appreciated. Especially during tumorigenesis, fibroblasts surrounding epithelial tumors, called Cancer Associated Fibroblasts (CAFs), produce diffusible factors (growth factors, inflammatory cytokines, chemokines and enzymes, and matrix metalloproteinases) that mediate inflammation either directly or indirectly through paracrine signaling between stroma and epithelial cancer cells. The risk of skin cancer increases exponentially with age. As a likely link between the two, senescence of fibroblasts results in production of the senescence-messaging-secretome (SMS), a panel of diffusible factors inducing paracrine growth stimulation, inflammation, and matrix remodeling. Interestingly, induction of these genes is also a characteristic of Cancer Associated Fibroblasts (CAFs). However, the link between the two cellular events, senescence and CAF activation is largely unexplored. ATF3 is a key stress response transcription factor with highly cell type specific functions, which has been discovered as a tumor promoter in keratinocytes in our lab. However, the biological and biochemical function of ATF3 in the dermal compartment of the skin has not been studied yet. Recently, we found that compromised Notch/CSL signaling in dermal fibroblasts (DFs) in mice is a primary cause of multifocal keratinocyte tumors called field cancerization associated with stromal atrophy, matrix alterations and inflammation. Further studies showed that CSL functions as a negative regulator of genes involved in DFs senescence and CAF activation. Here, we show that deletion or silencing of the ATF3 gene in DFs activates senescence and CAF-related gene expression similar to that triggered by loss of CSL, while increased ATF3 suppresses these changes. We hypothesize that ATF3 plays a suppressing role in CAF activation and keratinocyte tumor progression, overcoming the consequences of compromised Notch/CSL signaling. In support of this hypothesis, we found that loss of ATF3 in DFs promotes tumorigenic behavior of keratinocytes via negative control of cytokines, matrix-remodeling enzymes and cancer-associated proteins, possibly through direct binding to Notch/CSL targets, IL6 and Hes genes. On the other hand, in human clinical samples, stromal fields underlying premalignant actinic keratosis lesions showed significantly decreased ATF3 expression relative to stroma of flanking normal skin. Restoration of ATF3, which is lost in cancer development, may be used as a therapeutic tool for translational research to prevent or suppress the field cancerization process.

Femtosecond-laser assisted cataract surgery: a review.

Introduced in 2008, the femtosecond laser is a promising new technological advance which plays an ever increasing role in cataract surgery where it automates the three main surgical steps: corneal incision, capsulotomy and lens fragmentation. The proven advantages over manual surgery are: a better quality of incision with reduced induced astigmatism; increased reliability and reproducibility of the capsulotomy with increased stability of the implanted lens; a reduction in the use of ultrasound. Regarding refractive results or safety, however, no prospective randomized study to date has shown significant superiority compared with standard manual technique. The significant extra cost generated by this laser, undertaken by the patient, is a limiting factor for both its use and study. This review outlines the potential benefits of femtosecond-laser-assisted cataract surgery due to the automation of key steps and the safety of this new technology.

Stem cell transplantation in brain tumors: a new field for molecular imaging?

Neural stem cells have been proposed as a new and promising treatment modality in various pathologies of the central nervous system, including malignant brain tumors. However, the underlying mechanism by which neural stem cells target tumor areas remains elusive. Monitoring of these cells is currently done by use of various modes of molecular imaging, such as optical imaging, magnetic resonance imaging and positron emission tomography, which is a novel technology for visualizing metabolism and signal transduction to gene expression. In this new context, the microenvironment of (malignant) brain tumors and the blood-brain barrier gains increased interest. The authors of this review give a unique overview of the current molecular-imaging techniques used in different therapeutic experimental brain tumor models in relation to neural stem cells. Such methods for molecular imaging of gene-engineered neural stem/progenitor cells are currently used to trace the location and temporal level of expression of therapeutic and endogenous genes in malignant brain tumors, closing the gap between in vitro and in vivo integrative biology of disease in neural stem cell transplantation.