Les auteurs tiennent à remercier le personnel des installations d&#39;IRM à la Clinique de Semmes-Murphey, Memphis, Tennessee, ainsi que le département de neurochirurgie à l&#39;Université de Tennessee Health Science Center à Memphis, Tennessee.

1. Préparation du gel Phantoms et Dye <ol><li> Préparer un gel d&#39;agarose à 0,2% par dissolution de 2 g de poudre d&#39;agarose à 0,1% dans 1000 ml d&#39;eau désionisée. Agiter la solution pendant environ 1 minute pour assurer un mélange adéquat; et micro-ondes immédiatement la solution à intervalles de 3 minutes pour 9 min ou jusqu&#39;à ce qu&#39;il dégage, en remuant entre les intervalles. </li><li> Alors que le gel d&#39;agarose est liquide, verser la solution dans 5 cm x 5 cm x 5 cm conteneurs. Laisser de l&#39;espace dans la partie supérieure du récipient pour permettre à l&#39;eau et ajouter le gel d&#39;agarose à refroidir et décanter. </li><li> Une fois que le gel d&#39;agarose est solidifié (environ 1-2 heures), ajouter 1 cm d&#39;eau au-dessus du gel et réfrigérer. Il est préférable d&#39;utiliser le gel dans les 24-48 heures de mélange, mais il peut être stocké pendant jusqu&#39;à une semaine au réfrigérateur 10. </li><li> Préparer un colorant radio contraste dans une seringue de 60 ml composé de 50 ml de 0,017% bromophénol colorant bleu (BPB), et 2 mM de gadotéridol médias radio contraste. <ol><li> Mélanger 8,5 mg de BPB colorant à 50 ml d&#39;eau déminéralisée pour créer une solution BPB 0,017%. </li><li> Ajouter 0,2 ml de stock de 0,5 M gadotéridol à la solution BPB 50 ml 0,017% pour créer une solution de gadotéridol 2 mM. </li></ol></li></ol> 2. Préparation du système de perfusion <ol><li> Système de perfusion de la pompe à seringue (méthode préférée): Pour la préparation de la pompe à seringue, joindre le cathéter de perfusion directement à la seringue à travers le capteur de pression, en réduisant le volume mort de la ligne de perfusion. La fonction de purge de la pompe à seringue peut être utilisée pour dégager la ligne de l&#39;air à l&#39;aide d&#39;un bol plus grand que le volume d&#39;amorçage du cathéter à un débit de 10 ul / min. </li><li> Système de perfusion de la pompe à tube (méthode alternative): connexion de la seringue contenant le colorant de contraste radio à la pompe de perfusion. Attacher le capteur de pression à la sortie de la pompe avec le transducteur attaché au moniteur IV. Attacher un cathéter de perfusion 16 G à l&#39;extrémité ouverte du capteur de pression. Remarque: La pointe du cathéter de perfusion G 16 a un diamètre intérieurmètre de 0,2 mm et un diamètre extérieur de 0,35 mm. L&#39;embout est réalisé en silice fondue et la longueur de la pointe est de 3 mm. Il augmente à environ 0,75 mm et continue de 15 mm, le cathéter, puis accélère de façon conique de 1,6 mm ou 16 G. </li><li> Préparer pour perfusion en purgeant le système pendant environ 15 min à 16.667 l / min pour éliminer les bulles d&#39;air. Ne pas dépasser le débit 16,667 pi / min, que la machine cessera perfusion en raison de la haute pression de ligne. À la suite de la fixation du cathéter de perfusion à la ligne sortant de la pompe à perfusion, lignes de purge d&#39;air à l&#39;aide de la fonction &quot;bolus&quot; de la pompe à perfusion. </li><li> Fixer le support du cathéter de perfusion et le cadre trajectoire au conteneur gel fantôme (5 cm x 5 cm x 5 cm) et sa place dans la IRM. </li></ol> 3. DEC Gel perfusion et M. balayage <ol><li> Zéro la valeur de pression (mmHg) enregistrées par le moniteur de IV avant de commencer la perfusion. </li><li> Insérer le cathéter de perfusion dans le gel d&#39;agarose wvec la pompe à perfusion en cours d&#39;exécution au débit le plus faible possible, dans ce cas, 1.667 pi / min. </li><li> Commencer l&#39;analyse de M., en utilisant les paramètres indiqués dans le tableau 1, et la perfusion continue à un taux de 1,667 pi / min. Infuser le gel à une vitesse constante jusqu&#39;à ce que le volume total perfusé atteint 60 pi (environ 38 min). </li><li> Scannez le gel continu en 3 min et 50 seconde d&#39;intervalle. Enregistrer les lectures de pression toutes les 60 secondes. Une fois le volume perfusé atteint 60 pi, éteignez la pompe à perfusion; et la numérisation de M. complet tout en continuant à enregistrer des lectures de pression. </li></ol> 4. Analyse des données MR <ol><li> Pour l&#39;analyse des images IRM, utiliser une visionneuse DICOM approprié avec des fonctionnalités ROI de segmentation. </li><li> Sélectionner la trame correcte dans chaque balayage marqué par la section transversale du cathéter comme on le voit sur ​​la figure 1. </li><li> Utilisation du &quot;retour sur investissement - rectangle&quot; outil, sélectionnez la plus grande partie du gel qui n&#39;inclut paspartie du site de perfusion. La volonté de sortie du logiciel une densité de pixels de moyenne avec un écart type. Trouver la valeur qui correspond à trois écarts types de la moyenne. Cette valeur est utilisée comme seuil pour déterminer quand le contraste est présent à un niveau de confiance de 99,7%. </li><li> Utilisation du &quot;retour sur investissement - cercle&quot; outil, encercler le site de perfusion avec un grand cercle assez et donner ce un nom unique. </li><li> Sélectionnez le cercle et en utilisant le &quot;ROI - définir des valeurs de pixels à&quot; outil, la valeur de seuil d&#39;entrée trouvée dans l&#39;étape 4.3 en &quot;si la valeur actuelle est supérieure à:&quot; boîte et cochez cette ligne uniquement. Puis, dans &quot;à cette nouvelle valeur:&quot;, entrez une valeur élevée (25 000). Réinitialiser la densité de pixels pour sélectionner la zone couverte par le seuil préalablement défini. </li><li> Ensuite, en utilisant le &quot;ROI - développer la région (2D/3D segmentation)&quot; outil, sélectionnez 2D région de plus en plus, l&#39;algorithme de confiance avec le paramètre de rayon initial = 2, et brosse ROI. Cliquer à l&#39;intérieur du site de perfusion pour le logiciel pour calculer l&#39;aire totale of cette région. </li><li> En supposant une perfusion nuage sphérique, calculer le volume de diffusion de la région par l&#39;intermédiaire de l&#39;équation suivante: V = 4/3π (√ (Région / π)) 3 </li></ol>

<ol>
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Les auteurs déclarent qu&#39;ils n&#39;ont aucun intérêt financier concurrents.

<html> Les étapes essentielles pour assurer le succès de la perfusion sont: la purge de la ligne de perfusion de l&#39;air, en mélangeant le gel d&#39;agarose, l&#39;analyse des données de RM, l&#39;utilisation de petits diamètres de cathéter interne, en utilisant des gradins des conceptions de cathéters pour réduire au minimum le reflux, et en minimisant la pression ressentie par l&#39; gel ou de tissu dans lequel le médicament est perfusé. Comme indiqué précédemment, le principal détriment de la réussite...

livraison de convection-enhanced (CED) a été proposée comme une option de traitement pour un large éventail de troubles neurologiques, y compris les tumeurs malignes du cerveau, l&#39;épilepsie, les troubles métaboliques, les maladies neurodégénératives (comme la maladie de Parkinson) 1, le coup et traumatisme 2. DEC emploie flux massique à pression positive pour la distribution d&#39;un médicament ou d&#39;une autre solution de perfusion. DEC fournit une livraison sûre, fiable et homogène des composés de poids moléculaire, allant de faible à élevé, à des volumes cliniquement pertinentes 3. L&#39;administration de médicaments traditionnels aux tissus du cerveau est sévèrement limitée par la barrière hémato-encéphalique 4. Formé par les jonctions serrées entre les cellules endothéliales qui forment les capillaires dans le cerveau, les blocs barrière hémato-encéphalique et polaire des molécules de haut poids moléculaire de pénétrer dans le parenchyme du cerveau. Direct perfusion cérébrale intraparenchymateuse par DEC peut surmonter les limites des thérapeutiques modalités de délivrance de médicaments précédentset permet l&#39;utilisation d&#39;agents thérapeutiques qui ne serait pas traverser la barrière hémato-encéphalique, et ont donc été disponibles auparavant comme options de traitement viables 5. Les chercheurs de l&#39;US National Institutes of Health (NIH) ont décrit DEC dans les années 1990 comme un moyen de réaliser de plus grandes concentrations thérapeutiques que par diffusion seul 6-8. Les premières méthodes de CED impliqués implantation d&#39;un ou plusieurs cathéters dans le cerveau, la connexion d&#39;une pompe de perfusion vers le cathéter, et le pompage des agents thérapeutiques directement dans la région ciblée. La fraction accrue de la distribution et de la concentration relativement stable est rapporté à se produire lorsque la pression positive créée par la pompe de perfusion des tissus provoque une dilatation et permettent la perméation du médicament 9. La technique fondamentale pour CED reste largement la même comme il a été décrit pour la première. Les progrès de la conception du cathéter 10, la technique de perfusion <sup&gt; 11, contrôle de la pression de la ligne 2, et le suivi de l&#39;IRM en temps réel pour corriger cerveau quart de 12, 13, optimiser plusieurs perfusions colinéaires 14, et de surveiller la perte infusat 15 ont augmenté la sécurité et l&#39;efficacité du traitement 10. Une importance accrue a été accordée à la conception du cathéter et de la stratégie de perfusion, y compris débit. Successful DEC, avec reflux limité de cathéter et des dommages aux tissus, a été corrélée avec la conception de cathéter et la vitesse de perfusion. L&#39;utilisation d&#39;un cathéter avec un petit diamètre et un faible taux de perfusion de limiter le refoulement le long de l&#39;interface cerveau-cathéter ainsi que de limiter les dommages à l&#39;extrémité du cathéter 16. L&#39;IRM permet la confirmation visuelle de l&#39;emplacement correct pour le placement du cathéter de perfusion, et donc l&#39;administration de médicaments, tout en permettant également la correction des reflux d&#39;infusion ou la livraison aberrante 17. Images IRM peuvent également être utilisés pour se rapprocher et de suivre les volumes de distribution (Vd) Du médicament perfusé. Le Vd est calculée en utilisant une valeur d&#39;intensité du signal d&#39;imagerie par RM supérieure à trois écarts types au-dessus de la moyenne à partir du gel non infuse entourant comme un seuil pour la segmentation 18. Le Vd est une mesure utile pour DEC, car elle représente le volume du médicament distribué dans le cerveau. Avec le volume perfusé (Vi), un rapport peut être généré (Vd / Vi) quantifier le volume couvert par le médicament perfusé. Fantômes de gel d&#39;agarose imitent plusieurs propriétés mécaniques essentielles du cerveau humain importants pour la compréhension de DEC telles que: Vd, interactions gel cathéter, propriétés poro-élastiques, et perfusion nuage morphologie 10. Il a été démontré mélanges de gel d&#39;agarose 0,2% à imiter les changements in vivo de la fraction des pores locale causés par gel dilatation due à DEC. Une fraction de pores similaire à cerveau humain favorise les interactions similaires et des mesures précises de Vd 19. En outre, des concentrations similaires d&#39;ungarose tels que des gels de 0,6% et 0,8% ont montré des profils de pression de perfusion du cerveau similaires à 20. En outre, les gels d&#39;agarose translucides offrent l&#39;avantage de visualisation en temps réel de la pose du cathéter et de la perfusion un reflux. Fantômes de gel d&#39;agarose sont relativement peu coûteux à produire. Le coût des fantômes de gel d&#39;agarose peut être la clé de la formation future répandue dans la chirurgie neurologique. En raison de ces propriétés, les gels d&#39;agarose fournissent un substitut utile, reproduisant un grand nombre des principaux attributs de perfusion du cerveau humain, sans l&#39;utilisation du tissu cérébral. Comme indiqué ci-dessus, guidée par l&#39;image CED dans les modèles de gel d&#39;agarose fournit un effet bénéfique méthode in vitro pour les tests, la recherche et la formation. Le but de cet article est de décrire comment recréer fantômes de gel d&#39;agarose, d&#39;esquisser des protocoles d&#39;essai et d&#39;analyse DEC appropriées, et de traiter les erreurs courantes rencontrées lors des perfusions de DEC pour le traitement des maladies neurologiques.

<table border="0" cellpadding="0" cellspacing="0" width="590">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:205px;">Prohance</td>
			<td style="width:71px;">Bracco</td>
			<td style="width:119px;"></td>
			<td style="width:195px;">Gadoteridol radio contrast media</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:205px;">Bromophenol Blue Dye</td>
			<td style="width:71px;">Biorad</td>
			<td style="width:119px;">161-0404</td>
			<td>Dye for infusate visualization</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:205px;">Agarose Gel Powder</td>
			<td style="width:71px;">Biorad</td>
			<td style="width:119px;">161-3101EDU</td>
			<td>Agarose powder for creating gels</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">Medrad Veris MR Vital Signs Monitor</td>
			<td style="width:71px;">Medrad</td>
			<td style="width:119px;"></td>
			<td>MR safe infusion pressure monitor</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">16 Gauge SmartFlow Catheter</td>
			<td style="width:71px;">SurgiVision</td>
			<td style="width:119px;"></td>
			<td>Infusion catheter</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">Medrad Continuum MR Infusion System</td>
			<td style="width:71px;">Medrad</td>
			<td style="width:119px;"></td>
			<td>MR safe infusion pump</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:205px;">SMART Frame MRI Guided Trajectory Frame</td>
			<td style="width:71px;">ClearPoint</td>
			<td style="width:119px;"></td>
			<td>Infusion catheter frame</td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:205px;">Osirix Imaging Software and DICOM Viewer</td>
			<td style="width:71px;">Osirix Imaging Software</td>
			<td style="width:119px;"></td>
			<td>OsiriX 32-bit DICOM Viewer</td>
		</tr>
	</tbody>
</table>

image-guided convection-enhanced delivery into agarose gel models of the brain

livraison de convection-enhanced (CED) a été proposée comme une option de traitement pour un large éventail de maladies neurologiques. Neuroinfusion cathéter DEC permet de écoulement de la masse de pression positive pour offrir de plus grandes quantités de produits thérapeutiques destinés à une cible intracrânienne que les méthodes d&#39;administration de médicaments traditionnels. L&#39;utilité clinique de vrai IRM temps guidé DEC (RCED) réside dans la capacité de cibler avec précision, surveiller le traitement et identifier les complications. Avec la formation, RCED est efficace et les complications peuvent être minimisés. Le modèle de gel d&#39;agarose du cerveau est un outil accessible pour les tests de DEC, la recherche et la formation. Cerveau simulé RCED permet en pratique de la chirurgie simulée, tout en fournissant une rétroaction visuelle de la perfusion. Analyse de perfusion permet le calcul de la fraction de distribution (Vd / Vi) permettant à l&#39;élève de vérifier la similitude du modèle par rapport aux tissus du cerveau humain. Cet article décrit notre gel d&#39;agarose cerveau fantôme et décrit moi importantetrics cours des protocoles de perfusion et d&#39;analyse de DEC tout en répondant aux pièges les plus courants rencontrés lors de la perfusion de DEC pour le traitement des maladies neurologiques.

Interprétation et analyse des infusions DEC impliquent plusieurs facteurs importants tels que la fraction de distribution et reflux infusat. Le calcul de la fraction de répartition dépend en grande partie sur le calcul de la Vd. Par conséquent interprétation précise des images IRM est essentielle. Nous proposons une méthode semi-automatique pour reproduire de façon fiable ces mesures énumérées ci-dessus. Ces méthodes déterminent objectivement la surface de section transversale du nuage de liquide infusé et...

Watch this Scientific Journal Video about Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain at JoVE.com

Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

livraison de convection-enhanced (CED) a été proposée comme une option de traitement pour un large éventail de maladies neurologiques. Afin de préparer les professionnels de la santé pour l&#39;adoption de DEC, les modèles de formation accessibles sont nécessaires. Nous décrivons l&#39;utilisation d&#39;un gel d&#39;agarose en tant que tel modèle du cerveau humain pour le test, la recherche et la formation.

Guidée par l&#39;image convection-enhanced livraison en modèles Agarose Gel du cerveau

Convection-enhanced delivery (CED) has been proposed as a treatment option for a wide range of neurological diseases. Neuroinfusion catheter CED allows ...

image-guided-convection-enhanced-delivery-into-agarose-gel-models

Research

JoVE Journal

Medicine

11.3K vues.  University of Tennessee Health Science Center.  livraison de convection-enhanced (CED) a été proposée comme une option de traitement pour un large éventail de maladies neurologiques. Afin de préparer les professionnels de la santé pour l'adoption de DEC, les modèles de formation accessibles sont nécessaires. Nous décrivons l'utilisation d'un gel d'agarose en tant que tel modèle du cerveau humain pour le test, la recherche et la formation. 

Vidéo: Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain

MRI and PET in Mouse Models of Myocardial Infarction

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ideal model for testing novel therapeutic strategies.
In vivo magnetic resonance imaging (MRI) gives excellent views of the heart noninvasively with clear anatomical detail, which can be used for accurate functional assessment. Contrast agents can provide basic measures of tissue viability but these are nonspecific. Positron emission tomography (PET) is a complementary technique that is highly specific for molecular imaging, but lacks the anatomical detail of MRI. Used together, these techniques offer a sensitive, specific and quantitative tool for the assessment of the heart in disease and recovery following treatment.
In this paper we explain how these methods are carried out in mouse models of acute myocardial infarction. The procedures described here were designed for the assessment of putative protective drug treatments. We used MRI to measure systolic function and infarct size with late gadolinium enhancement, and PET with fluorodeoxyglucose (FDG) to assess metabolic function in the infarcted region. The paper focuses on practical aspects such as slice planning, accurate gating, drug delivery, segmentation of images, and multimodal coregistration. The methods presented here achieve good repeatability and accuracy maintaining a high throughput.

We describe how to perform MRI and PET imaging of the mouse heart. The protocol is tailored to assess treatment efficacy in models of myocardial infarction and heart failure.

IRM et la TEP dans les modèles de souris de l&#39;infarctus du myocarde

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ...

Recherche

Médecine

Heterotopic Mucosal Engrafting Procedure for Direct Drug Delivery to the Brain in Mice

Delivery of therapeutics into the brain is impeded by the presence of the blood-brain barrier (BBB) which restricts the passage of polar and high molecular weight compounds from the bloodstream and into brain tissue. Some direct delivery success in humans has been achieved via implantation of transcranial catheters; however this method is highly invasive and associated with numerous complications. A less invasive alternative would be to dose the brain through a surgically implanted, semipermeable membrane such as the nasal mucosa that is used to repair skull base defects following endoscopic transnasal tumor removal surgery in humans. Drug transfer though this membrane would effectively bypass the BBB and diffuse directly into the brain and cerebrospinal fluid. Inspired by this approach, a surgical approach in mice was developed that uses a donor septal mucosal membrane engrafted over an extracranial surgical BBB defect. This model has been shown to effectively allow the passage of high molecular weight compounds into the brain. Since numerous drug candidates are incapable of crossing the BBB, this model is valuable for performing preclinical testing of novel therapies for neurological and psychiatric diseases.

A mouse model of human endoscopic skull base reconstruction has been developed that creates a semipermeable interface between the brain and nose using nasal mucosal grafts. This method allows researchers to study delivery to the central nervous system of high molecular weight therapeutics which are otherwise excluded by the blood-brain barrier when administered systemically.

Heterotopic muqueuse procédure de greffe de médicaments Livraison directe au cerveau chez les souris

Delivery of therapeutics into the brain is impeded by the presence of the blood-brain barrier (BBB) which restricts the passage of polar and high ...

Mouse Kidney Transplantation: Models of Allograft Rejection

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

Here, we present a protocol to study the immunology of rejection. The surgical model presented reports a short operating time and a concise technique. Depending on the donor-recipient strain combination, the transplanted kidney may develop acute cellular rejection or chronic allograft damage, defined by interstitial fibrosis and tubular atrophy.

Souris Transplantation rénale: Les modèles de rejet des allogreffes

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely ...

Transposon Mediated Integration of Plasmid DNA into the Subventricular Zone of Neonatal Mice to Generate Novel Models of Glioblastoma

An urgent need exists to test the contribution of new genes to the pathogenesis and progression of human glioblastomas (GBM), the most common primary brain tumor in adults with dismal prognosis. New potential therapies are rapidly emerging from the bench and require systematic testing in experimental models which closely reproduce the salient features of the human disease. Herein we describe in detail a method to induce new models of GBM with transposon-mediated integration of plasmid DNA into cells of the subventricular zone of neonatal mice. We present a simple way to clone new transposons amenable for genomic integration using the Sleeping Beauty transposon system and illustrate how to monitor plasmid uptake and disease progression using bioluminescence, histology and immuno-histochemistry. We also describe a method to create new primary GBM cell lines. Ideally, this report will allow further dissemination of the Sleeping Beauty transposon system among brain tumor researchers, leading to an in depth understanding of GBM pathogenesis and progression and to the timely design and testing of effective therapies for patients.

Here we describe an efficient and versatile protocol to induce, monitor and analyze novel glioblastomas (GBM) using transposon DNA injected into the ventricles of neonatal mice. Cells of the subventricular zone, which take up the plasmid, transform, proliferate and generate tumors with histo-pathological characteristics of human GBM.

Transposon Mediated intégration du plasmide ADN dans le zone sous-ventriculaire de souris néonatale pour générer des modèles nouveaux de glioblastome

An urgent need exists to test the contribution of new genes to the pathogenesis and progression of human glioblastomas (GBM), the most common primary ...

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) models based on pBECs in mono-culture (MC), MC with astrocyte-conditioned medium (ACM), and non-contact co-culture (NCC) with astrocytes of porcine or rat origin. pBECs were isolated and cultured from fragments of capillaries from the brain cortices of domestic pigs 5-6 months old. These fragments were purified by careful removal of meninges, isolation and homogenization of grey matter, filtration, enzymatic digestion, and centrifugation. To further eliminate contaminating cells, the capillary fragments were cultured with puromycin-containing medium. When 60-95% confluent, pBECs growing from the capillary fragments were passaged to permeable membrane filter inserts and established in the models. To increase barrier tightness and BBB characteristic phenotype of pBECs, the cells were treated with the following differentiation factors: membrane permeant 8-CPT-cAMP (here abbreviated cAMP), hydrocortisone, and a phosphodiesterase inhibitor, RO-20-1724 (RO). The procedure was carried out over a period of 9-11 days, and when establishing the NCC model, the astrocytes were cultured 2-8 weeks in advance. Adherence to the described procedures in the protocol has allowed the establishment of endothelial layers with highly restricted paracellular permeability, with the NCC model showing an average transendothelial electrical resistance (TEER) of 1249 &#177; 80 &#937; cm2, and paracellular permeability (Papp) for Lucifer Yellow of 0.90 10-6 &#177; 0.13 10-6 cm sec-1 (mean &#177; SEM, n=55). Further evaluation of this pBEC phenotype showed good expression of the tight junctional proteins claudin 5, ZO-1, occludin and adherens junction protein p120 catenin. The model presented can be used for a range of studies of the BBB in health and disease and, with the highly restrictive paracellular permeability, this model is suitable for studies of transport and intracellular trafficking.

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

The aim of the protocol is to present an optimized procedure for the establishment of an in vitro blood-brain barrier (BBB) model based on primary porcine brain endothelial cells (pBECs). The model shows high reproducibility, high tightness, and is suitable for studies of transport and intracellular trafficking in drug discovery.

Procédé amélioré pour la création d’un In Vitro barrière hémato - encéphalique modèle basé sur les cellules endothéliales du cerveau porcin

The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) ...

Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain

Insulin regulates systematic metabolism in the hypothalamus and the peripheral insulin response. An inflammatory reaction in peripheral adipose tissues contributes to type 2 diabetes mellitus (T2DM) development and appetite regulation in the hypothalamus. Chemokine CCL5 and C-C chemokine receptor type 5 (CCR5) levels have been suggested to mediate arteriosclerosis and glucose intolerance in type 2 diabetes mellitus (T2DM). In addition, CCL5 plays a neuroendocrine role in the hypothalamus by regulating food intake and body temperature, thus, prompting us to investigate its function in hypothalamic insulin signaling and the regulation of peripheral glucose metabolism.
The micro-osmotic pump brain infusion system is a quick and precise way to manipulate CCL5 function and study its effect in the brain. It also provides a convenient alternative approach to generating a transgenic knockout animal. In this system, CCL5 signaling was blocked by intracerebroventricular (ICV) infusion of its antagonist, MetCCL5, using a micro-osmotic pump. The peripheral glucose metabolism and insulin responsiveness was detected by the Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT). Insulin signaling activity was then analyzed by protein blot from tissue samples derived from the animals.
After 7-14 days of MetCCL5 infusion, the glucose metabolism and insulin responsiveness was impaired in mice, as seen in the results of the OGTT and ITT. The IRS-1 serine302 phosphorylation was increased and the Akt activity was reduced in mice hypothalamic neurons following CCL5 inhibition. Altogether, our data suggest that blocking CCL5 in the mouse brain increases the phosphorylation of IRS-1 S302 and interrupts hypothalamic insulin signaling, leading to a decrease in insulin function in peripheral tissues as well as the impairment of glucose metabolism.

This protocol studies the role of chemokine (C-C motif) ligand 5 (CCL5) in the hypothalamus by delivering an antagonist, MetCCL5, into the mouse brain using a micro-osmotic pump brain infusion system. This transient inhibition of CCL5 activity interrupted hypothalamic insulin signaling, leading to glucose intolerance and peripheral systemic insulin sensitivity.

Étudier le Signal hypothalamique de l’insuline à l’intolérance au Glucose périphérique avec un système de perfusion continue de drogues dans le cerveau de souris

Insulin regulates systematic metabolism in the hypothalamus and the peripheral insulin response. An inflammatory reaction in peripheral adipose tissues ...

Image-Guided Resection of Glioblastoma and Intracranial Implantation of Therapeutic Stem Cell-seeded Scaffolds

Glioblastoma (GBM), the most common and aggressive primary brain cancer, carries a life expectancy of 12-15 months. The short life expectancy is due in part to the inability of the current treatment, consisting of surgical resection followed by radiation and chemotherapy, to eliminate invasive tumor foci. Treatment of these foci may be improved with tumoricidal human mesenchymal stem cells (MSCs). MSCs exhibit potent tumor tropism and can be engineered to express therapeutic proteins that kill tumor cells. Advancements in preclinical models indicate that surgical resection induces premature MSC loss and reduces therapeutic efficacy. Efficacy of MSC treatment can be improved by seeding MSCs on a biodegradable poly(lactic acid) (PLA) scaffold. MSC delivery into the surgical resection cavity on a PLA scaffold restores cell retention, persistence, and tumor killing. To study the effects of MSC-seeded PLA implantation on GBM, an accurate preclinical model is needed. Here we provide a preclinical surgical protocol for image-guided tumor resection of GBM in immune-deficient mice followed by MSC-seeded scaffold implantation. MSCs are engineered with lentiviral constructs to constitutively express and secrete therapeutic TNF&#945;-related apoptosis-inducing ligand (TRAIL) as well as green fluorescent protein (GFP) to allow fluorescent tracking. Similarly, the U87 tumor cells are engineered to express mCherry and firefly luciferase, providing dual fluorescent/luminescent tracking. While currently used for investigating stem cell mediated delivery of therapeutics, this protocol could be modified to investigate the impact of surgical resection on other GBM interventions.

Tumor-seeking therapeutic mesenchymal stem cells (MSCs) show promise as a treatment for invasive glioblastoma. Optimal transplantation involves delivery of MSCs into the tumor resection cavity on scaffolds. Here, preclinical techniques to study MSC treatment of glioblastoma are provided including: image-guided tumor resection; implantation of MSC-seeded scaffolds; and postoperative therapy tracking.

Guidée par l’image de la résection du glioblastome et Implantation intracrânienne d’échafaudages de graines cellules souches thérapeutiques

Glioblastoma (GBM), the most common and aggressive primary brain cancer, carries a life expectancy of 12-15 months. The short life expectancy is due in ...

Predicting Treatment Response to Image-Guided Therapies Using Machine Learning: An Example for Trans-Arterial Treatment of Hepatocellular Carcinoma

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. The objective of this study was to develop a method to predict response to intra-arterial treatment prior to intervention.
The method provides a general framework for predicting outcomes prior to intra-arterial therapy. It involves pooling clinical, demographic and imaging data across a cohort of patients and using these data to train a machine learning model. The trained model is applied to new patients in order to predict their likelihood of response to intra-arterial therapy.
The method entails the acquisition and parsing of clinical, demographic and imaging data from N patients who have already undergone trans-arterial therapies. These data are parsed into discrete features (age, sex, cirrhosis, degree of tumor enhancement, etc.) and binarized into true/false values (e.g., age over 60, male gender, tumor enhancement beyond a set threshold, etc.). Low-variance features and features with low univariate associations with the outcome are removed. Each treated patient is labeled according to whether they responded or did not respond to treatment. Each training patient is thus represented by a set of binary features and an outcome label. Machine learning models are trained using N - 1 patients with testing on the left-out patient. This process is repeated for each of the N patients. The N models are averaged to arrive at a final model.
The technique is extensible and enables inclusion of additional features in the future. It is also a generalizable process that may be applied to clinical research questions outside of interventional radiology. The main limitation is the need to derive features manually from each patient. A popular modern form of machine learning called deep learning does not suffer from this limitation, but requires larger datasets.

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. A method for predicting response to these therapies is proposed. The technique uses pre-procedural clinical, demographic, and imaging information to train machine learning models capable of predicting response prior to treatment.

Prédire la réponse au traitement aux thérapies guidées par l’Image à l’aide de Machine Learning : un exemple pour le Trans-artériel traitement du carcinome hépatocellulaire

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. The objective of this ...

An Image Guided Transapical Mitral Valve Leaflet Puncture Model of Controlled Volume Overload from Mitral Regurgitation in the Rat

Mitral regurgitation (MR) is a widely prevalent heart valve lesion, which causes cardiac remodeling and leads to congestive heart failure. Though the risks of uncorrected MR and its poor prognosis are known, the longitudinal changes in cardiac function, structure and remodeling are incompletely understood. This knowledge gap has limited our understanding of the optimal timing for MR correction, and the benefit that early versus late MR correction may have on the left ventricle. To investigate the molecular mechanisms that underlie left ventricular remodeling in the setting of MR, animal models are necessary. Traditionally, the aorto-caval fistula model has been used to induce volume overload, which differs from clinically relevant lesions such as MR. MR represents a low-pressure volume overload hemodynamic stressor, which requires animal models that mimic this condition. Herein, we describe a rodent model of severe MR in which the anterior leaflet of the rat mitral valve is perforated with a 23G needle, in a beating heart, with echocardiographic image guidance. The severity of MR is assessed and confirmed with echocardiography, and the reproducibility of the model is reported.&#160;&#160;

A rodent model of left heart volume overload from mitral regurgitation is reported. Mitral regurgitation of controlled severity is induced by advancing a needle of defined dimensions into the anterior leaflet of the mitral valve, in a beating heart, with ultrasound guidance.&#160;

Une image guidée Transapical Mitral Valve Leaflet Perforation Modèle de surcharge de volume contrôlé de la régurgitation mitrale dans le rat

Mitral regurgitation (MR) is a widely prevalent heart valve lesion, which causes cardiac remodeling and leads to congestive heart failure. Though the ...

Intratracheal Administration of Dry Powder Formulation in Mice

In the development of inhalable dry powder formulations, it is essential to evaluate their biological activities in preclinical animal models. This paper introduces a noninvasive method of intratracheal delivery of dry powder formulation in mice. A dry powder loading device that consists of a 200 &#181;L gel loading pipette tip connected to an 1 mL syringe via a three-way stopcock is presented. A small amount of dry powder (1-2 mg) is loaded into the pipette tip and dispersed by 0.6 mL of air in the syringe. Because pipette tips are disposable and inexpensive, different dry powder formulations can be loaded into different tips in advance. Various formulations can be evaluated in the same animal experiment without device cleaning and dose refilling, thereby saving time and eliminating the risk of cross-contamination from residual powder. The extent of powder dispersion can be inspected by the amount of powder remaining in the pipette tip. A protocol of intubation in mouse with a custom-made light source and a guiding cannula is included. Proper intubation is one of the key factors that influences the intratracheal delivery of dry powder formulation to the deep lung region of the mouse.

Dry powder formulations for inhalation have great potential in treating respiratory diseases. Before entering human studies, it is necessary to evaluate the efficacy of the dry powder formulation in preclinical studies. A simple and noninvasive method of the administration of dry powder in mice through the intratracheal route is presented.

Administration intratrachéale de formulation de poudre sèche chez la souris

In the development of inhalable dry powder formulations, it is essential to evaluate their biological activities in preclinical animal models. This paper ...