Abbiamo gentilmente Ringraziamo i membri aggiuntivi del Lever Lab che hanno contribuito alla raccolta dei dati (Andries Ferreira, Danarae Aleman, Alexis Mok, Kaitlin Flynn, Elizabeth Bearce, e Matan Kadosh) e revisione del manoscritto (Andries Ferreira, Rebecca Schneider, e Kate Robbins). Riconosciamo inoltre Roderic Schlotzhauer e Edwin Honse dal MU Fisica Machine Shop per il loro contributo la progettazione e la fabbricazione di tubi di osservazione roditori utilizzati in questo studio. Siamo particolarmente riconoscenti Malea Jan Kunkel (Radiologia Supervisor in Medicina Veterinaria e Chirurgia Dipartimento presso l&#39;Università del Missouri - College di Medicina Veterinaria) e Jan Ivey (Responsabile del Animal Research Cath Lab dell&#39;Università del Missouri - Facoltà di Medicina) per dimostrare la pazienza costante e motivazione durante il funzionamento i fluoroscopes ad alta energia, come abbiamo sviluppato il protocollo VFSS murino. Fonti di finanziamento per questo studio includeva NIH / NIDCD (TE Lever), NIH / NINDS (GK Pavlath), Otolaryngofondi Head and Neck Surgery start-up (TE leva), MU PRIME Fondo (TE Lever), Mizzou Advantage (TE Lever), e il Centro di MU on Aging (TE Lever) - logia.

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</ol>

Open Access per questo articolo è sponsorizzato da Glenbrook.

La disfagia (deglutizione impairment) è un sintomo comune di numerose condizioni di salute che interessano le persone di tutte le età. Gli esempi includono ictus, morbo di Parkinson, il morbo di Alzheimer, la paralisi cerebrale, distrofia muscolare, sclerosi laterale amiotrofica (SLA), malattia di Batten, della testa e del collo, nascita prematura, e l&#39;invecchiamento avanzato. Disfagia è fortemente correlata con la mortalità, tipicamente come conseguenza di malnutrizione grave o polmonite batterica che si sviluppa quando carichi alimentare / liquido / saliva viene aspirato nei polmoni 1-4. Questa condizione medica debilitante e pericolosa per la vita colpisce oltre 15 milioni di persone ogni anno negli Stati Uniti da soli 3. Nonostante l&#39;alta prevalenza e gli esiti negativi associati, attuali opzioni di trattamento per la disfagia sono limitati a palliative (piuttosto che curativo) approcci, come la modificazione della dieta (per esempio, evitando specifiche consistenze cibo / liquidi), cambiamenti posturali (ad esempio, Tucking mento durante la deglutizione), approcci motore (ad esempio, esercita il targeting muscoli nella cavità orale, faringe e laringe), approcci sensoriali (ad esempio, il sapore di attuazione, la temperatura, stimolazione e / o meccanico), e il tubo di alimentazione (ad esempio, la nutrizione e idratazione somministrato per via nasogastrica (NG) tubo o gastrostomia endoscopica percutanea (PEG) tube). Questi trattamenti servono soltanto come terapia sintomatica, piuttosto che prendere di mira le cause di fondo del problema. Infatti, uno dei principali ostacoli alla scoperta di nuovi, trattamenti efficaci per la disfagia è la conoscenza scientifica limitata dei meccanismi patologici responsabili, che sono probabilmente diverso per ogni malattia. Diagnosi disfagia è prevalentemente realizzato utilizzando una procedura radiografica chiamata videofluoroscopia deglutizione studio (VFSS), noto anche come studio bario modificato. Nel corso degli ultimi 30 e più anni, questo test diagnostico è stato considerato il gold-standard per evaluating funzione rondine 5-7. Questo test comporta avere il paziente seduto o in piedi all&#39;interno del percorso del fascio di raggi X di una macchina fluoroscopia mentre l&#39;ingestione volontaria di cibo e consistenze liquidi mescolati con un mezzo di contrasto per via orale, di solito solfato di bario 8,9 o ioexolo 10. Come il paziente inghiotte, cibo e liquidi contenenti mezzo di contrasto può essere visto in tempo reale tramite un monitor di un computer durante il viaggio dalla bocca allo stomaco. Strutture dei tessuti molli sono visibili e possono essere valutati rispetto alla struttura e funzione. Ai pazienti viene chiesto di eseguire diverse rondini di ogni alimento e consistenza liquida, che sono tutti video registrato per la successiva visualizzazione e l&#39;analisi fotogramma per fotogramma per quantificare la presenza e il grado di disfagia. Numerosi componenti fisiologiche di deglutizione sono tipicamente analizzati, come il punto anatomica grilletto della rondine faringea, tempo di transito del bolo attraverso la faringe e dell&#39;esofago, la portata e la durata della LarynGEAL elevazione, la posizione e la quantità di residui post-rondine, e la presenza e la ragione fisiologica per aspirazione 7,11. Aspetti del protocollo VFSS umana sono stati recentemente adattati per lo studio ratti liberamente comportano; Tuttavia, i risultati sono stati limitati perché i topi non sono rimasti nel campo videofluoroscopia di vista durante i test 12. VFSS non è stata tentata con i topi. Adattamento di successo del protocollo VFSS umana per l&#39;uso con i topi e ratti potrebbe fornire un metodo di ricerca romanzo di indagare le centinaia di murino attualmente esistenti (topi e ratti) modelli di malattie che sono noti per causare disfagia negli esseri umani. Questo nuovo metodo (di seguito anche VFSS murine) sarebbe quindi accelerare l&#39;identificazione e la validazione di modelli murini di disfagia che sono adatti per lo studio dei meccanismi neurofisiologici alla base all&#39;interno dei tessuti muscolari, i nervi, e il cervello che sono patologici e contribuire alla disfagia in uomo. Inoltre, murino VFSS consentirebbe l&#39;identificazione delle misure oggettive (biomarkers) di funzione di rondine / disfunzioni che potrebbero essere confrontato direttamente con gli esseri umani. Questi incrociati specie biomarcatori videofluoroscopia potrebbero poi servire misure di esito in quanto nuovi per quantificare l&#39;efficacia del trattamento in studi preclinici con i topi e ratti, che meglio tradurre a sperimentazioni cliniche con le persone. A tal fine, il protocollo VFSS murino è stata stabilita utilizzando ~ 100 topi di entrambi i sessi. Tutti i topi erano o C57 o ibridi C57 / SJL ceppi. I topi C57 non sono stati geneticamente modificati, mentre C57 / SJL era il ceppo sfondo per una colonia di transgenico SOD1-G93A (o SOD1) topo, il modello animale più diffuso della SLA. La colonia SOD1 è un approssimativo 50-50 mix di transgenici (cioè ALS colpiti) topi e nontransgenic (cioè, non affetti) fratellini. Il protocollo VFSS murino costituito da tre componenti: <ol><li&gt; camere di osservazione su misura che consentono l&#39;alimentazione volontaria e deglutizione in piedi sfrenato in uno spazio confinato all&#39;interno di una macchina fluoroscopia, </li><li> Ricette che mascherano la avversiva gusto / odore di mezzi di contrasto per via orale e producono radiodensity sufficiente per consentire un&#39;adeguata visualizzazione di deglutizione, </li><li> Un protocollo step-by-step test che massimizza il rispetto degli animali, riduce al minimo il tempo totale di prova e di esposizione alle radiazioni, e permette la quantificazione dei diversi parametri di rondine per ogni fase di deglutizione (cioè, per via orale, della faringe, dell&#39;esofago e). </li></ol> L&#39;effetto combinato produce un comodo basso stress, ambiente esame, auto-alimentazione che consente di valutare l&#39;alimentazione tipica e deglutizione comportamenti dei topi.

<table><tbody><tr><td>Polycarbonate tubing for observation chambers</td><td>McMaster-Carr</td><td>3161T41</td><td>Body of observation tubes, 2&quot;X2&quot; diameter, 0.080&quot; thick wall</td></tr><tr><td>Polycarbonate sheet&amp;nbsp; for observation chambers</td><td>McMaster-Carr</td><td>9115K71</td><td>End-caps for observation tubes, 2&quot;x12&quot;x3/4&quot;</td></tr><tr><td>Polycarbonate sheet&amp;nbsp; for observation chambers</td><td>McMaster-Carr</td><td>8574K281</td><td>Peg-bowls for observation tubes</td></tr><tr><td>Silicone O-rings&amp;nbsp; for end-caps of observation chambers</td><td>McMaster-Carr</td><td>9396K108</td><td>S1138 AS568-029, pack of 25&lt;br/&gt; http://www.mcmaster.com/#o-rings/=t0wt5r&amp;nbsp;</td></tr><tr><td>Silicone stoppers for observation chambers</td><td>McMaster-Carr</td><td>2903K22</td><td>Package of 10 stoppers to plug the oval opening in the top of the observation chamber when using a peg-bowl&lt;br/&gt; http://www.mcmaster.com/#catalog/120/3803/=t0y5at</td></tr><tr><td>Centrifuge tubes for sipper tube bottles</td><td>Evergreen Scientific</td><td>222-3530-G80</td><td>30 ml freestanding centrifuge tubes, with caps, sterile&lt;br/&gt; https://www.evergreensci.com/labware-catalog/tubes-and-vials/30-and-50-ml-centrifuge-tubes/&amp;nbsp;</td></tr><tr><td>Silcone stoppers for sipper tube bottles</td><td>Saint-Gobain Performance Plastics</td><td>DX263031-10&amp;nbsp;</td><td>Number 31D, size: 26 mm bottom, 32 mm top, 30 mm high; 10 pack;&amp;nbsp;&lt;br/&gt; http://www.labpure.com/en/Products.asp?ID=179&amp;amp;PageBrand=STOPPERS</td></tr><tr><td>Stopper borers for sipper tube bottles</td><td>Thomas Scientific</td><td>3276G40</td><td>Cork Borer Set that ranges from 3/16-15/16 inch&amp;nbsp;&lt;br/&gt; http://www.thomassci.com/Supplies/Corks/_/CORK-BORER-SET-316-1516-IN?q=Humboldt</td></tr><tr><td>Drinking tubes for sipper tube bottles</td><td>Ancare</td><td>TD-100&amp;nbsp;</td><td>2 1/2&amp;rdquo; long drinking tubes with 5/16&amp;rdquo; opening, straight ball-spout&lt;br/&gt; http://www.ancare.com/products/watering-equipment/open-drinking-tubes/straight-tubes-ball-point&amp;nbsp;</td></tr><tr><td>Iohexol for making oral contrast agent solution</td><td>GE Healthcare</td><td></td><td>350 mg iodine per ml&lt;br/&gt; http://www3.gehealthcare.com/en/products/categories/contrast_media/omnipaque&amp;nbsp;</td></tr><tr><td>Chocolate syrup for flavoring oral contrast agent</td><td>Herseys</td><td></td><td></td></tr><tr><td>10 ml syringe for syringe delivery system</td><td>Becton, Dickinson and Company</td><td>309604</td><td>Luer lock tip syringe without needle, 100 per box&lt;br/&gt; http://www.bd.com/hypodermic/products/syringeswithoutneedles.asp</td></tr><tr><td>Catheter tubing for syringe delivery system</td><td>Becton, Dickinson and Company</td><td>427451</td><td>Polyethylene Tubing (Non-Sterile) (PE 240) 100&#039;&lt;br/&gt; http://www.bd.com/ds/productCenter/427451.asp&amp;nbsp;</td></tr><tr><td>Needle for syringe delivery system</td><td>Becton, Dickinson and Company</td><td>427560</td><td>15-gauge needle, fits into PE 240 catheter tubing&lt;br/&gt; http://www.bd.com/ds/productCenter/427560.asp&amp;nbsp;</td></tr><tr><td>Delrin acetal resin rod for syringe delivery system</td><td>McMaster-Carr</td><td>8576K15</td><td>1/2 inch diameter, black&lt;br/&gt; http://www.mcmaster.com/#catalog/120/3609/=t0wvaf&amp;nbsp;</td></tr><tr><td>Acrylic sheeting for scissor lift</td><td>Ponoko</td><td></td><td>Laser cut&lt;br/&gt; http://www.ponoko.com&amp;nbsp;</td></tr><tr><td>3D printed ABS frame</td><td>Engineering Rapid Prototyping Facility, University of Missouri</td><td></td><td></td></tr><tr><td>Brass rods for scissor lift</td><td>Amazon</td><td>TTRB-03-12-03</td><td>made into axles&lt;br/&gt; http://www.amazon.com/Brass-Seamless-Round-Tubing-Length/dp/B000FN898M</td></tr><tr><td>Drawer slide for scissor lift</td><td>Richelieu</td><td>10292G116</td><td>Attaches to base of scissor lift&lt;br/&gt; http://www.lowes.com/pd_380986-93052-T35072G16_0__?productId=50041754</td></tr><tr><td>28BYJ-48 stepper motor for scissor lift</td><td></td><td></td><td>2 each</td></tr><tr><td>ULN2003 Darlington transistor array for scissor lift</td><td>Toshiba</td><td>ULN2003APG</td><td>Used as stepper drivers (2 each)</td></tr><tr><td>ATTINY85 microcontroller for scissor lift</td><td>Atmel</td><td>ATTINY85-20PU</td><td>2 each&lt;br/&gt; http://www.taydaelectronics.com/attiny85-attiny85-20pu-8-bit-20mhz-microcontroller-ic.html</td></tr><tr><td>Nylon spur gear</td><td>McMaster-Carr</td><td>57655K34</td><td>2 each&lt;br/&gt; http://www.mcmaster.com/#57655k34/=t0yaqz</td></tr><tr><td>Nylon spur gear rack</td><td>McMaster-Carr</td><td>57655K62</td><td>2 each&lt;br/&gt; http://www.mcmaster.com/#57655k62/=t0ybh9</td></tr><tr><td>4-40 nylon machine screws</td><td>McMaster-Carr</td><td>95133A315</td><td>Lift assembly&lt;br/&gt; http://www.mcmaster.com/#95133a315/=t0yd8q</td></tr><tr><td>4-40 nylon hex nuts</td><td>McMaster-Carr</td><td>94812A200</td><td>Lift assembly&lt;br/&gt; http://www.mcmaster.com/#94812a200/=t0ye29</td></tr><tr><td>Buna-N O-Ring AS568A Dash No. 104</td><td>McMaster-Carr</td><td>9452K318</td><td>Lift assembly&lt;br/&gt; http://www.mcmaster.com/#9452k318/=t0yem7</td></tr><tr><td></td><td></td><td></td><td></td></tr></tbody></table>

adapting human videofluoroscopic swallow study methods to detect and characterize dysphagia in murine disease models

Questo studio adattato videofluoroscopia umana deglutizione studio (VFSS) metodi per l&#39;utilizzo con modelli di malattia murini al fine di facilitare la ricerca traslazionale disfagia. I risultati di successo dipendono tre componenti critici: camere di prova che permettono di auto-alimentazione, mentre in piedi sfrenato in uno spazio ristretto, le ricette che mascherano la avversiva gusto / odore di mezzi di contrasto per via orale disponibili in commercio, e un protocollo di step-by-step test che consente la quantificazione di rondine fisiologia. Eliminazione di uno o più di questi componenti avranno un impatto negativo sui risultati dello studio. Inoltre, la capacità di livello di energia del sistema di fluoroscopia determinerà che ingoiare parametri può essere esaminato. La maggior parte dei centri di ricerca hanno fluoroscopes alta energia progettati per essere utilizzati con le persone e gli animali più grandi, che si traduce in eccezionalmente scarsa qualità delle immagini durante il test di topi e altri piccoli roditori. Nonostante questa limitazione, abbiamo identificato sette VFSParametri S che sono costantemente quantificabili in topi quando si utilizza un fluoroscopio alta energia in combinazione con il nuovo protocollo VFSS murino. Recentemente abbiamo ottenuto un sistema a bassa fluoroscopia energetico con capacità eccezionalmente alta di imaging e di ingrandimento che è stato progettato per l&#39;uso con topi e altri piccoli roditori. Operazioni preliminari con questo nuovo sistema, in combinazione con il nuovo protocollo VFSS murino, ha identificato 13 parametri di rondine che sono costantemente quantificabile nei topi, che è quasi il doppio del numero ottenuto con convenzionali (cioè ad alta energia) fluoroscopes. Individuazione di parametri aggiuntivi rondine è atteso come ottimizziamo le capacità di questo nuovo sistema. Risultati finora dimostrano l&#39;utilità di utilizzare un sistema di fluoroscopia a bassa energia per rilevare e quantificare i cambiamenti sottili rondine fisiologia che potrebbero altrimenti essere trascurati quando si utilizza fluoroscopes alta energia per studiare modelli di malattia murini.

Abbiamo progettato con successo un romanzo e replicabile protocollo VFSS specifici murino che include camere di prova che permettono di auto-alimentazione, ricette per aromatizzanti agenti di contrasto per via orale, e un protocollo di step-by-step test che consente di quantificare rondine fisiologia. La capacità di livello di energia del sistema di fluoroscopia determinato che ingoiare parametri potrebbero essere studiate in topi. Inizialmente abbiamo usato fluoroscopes alta energia progettati per essere utilizzati con le persone e gli animali più grandi (ad esempio, GE Advantx, GE OEC 9600, e Omega Cardiac Cath CS-25, ciascuna a 30 fotogrammi al secondo). Tuttavia, questi sistemi hanno avuto capacità di ingrandimento insufficienti per i topi di prova, che ha portato il riempimento animali solo una piccola porzione del campo visivo (Figura 9). Come risultato, la qualità dell&#39;immagine era eccezionalmente scarsa, rendendo impossibile visualizzare maggior parte delle strutture del meccanismo di deglutizione. Nonostante questa limitazione, abbiamo identificato 7 obiettivo VFSS rondine parametri che sono stati costantemente quantificabili per i topi quando si utilizza un convenzionale (cioè, alta energia) fluoroscopio in combinazione con il nuovo protocollo VFSS murino (Tabella 3). Inoltre, abbiamo identificato lo spazio vallecula come punto di trigger anatomica per la deglutizione in topi adulti sani (3-17 mesi di età), così come i topi con le condizioni di età avanzata (&gt; 18 mesi) e SLA allo stadio terminale. <img alt="Figura 9" src="/files/ftp_upload/52319/52319fig9highres.jpg" width="650" /> Figura 9:. High Energy fluoroscopia Sistemi Sinistra: immagine Rappresentante di un mouse ottenuto con alta energia (ad esempio, i sistemi convenzionali) fluoroscopia. Si noti che il mouse riempie solo una piccola porzione del campo di vista fluoroscopia, dimostrando così la capacità di ingrandimento insufficiente fluoroscopes convenzionali per roditori imaging. Destra: Stessa immagine ingrandita post-capture utilizzando un programma software di editing video. Freccia nera: ingoiare punto di trigger (vallecule). Freccia bianca:. Bolo nell&#39;esofago distale, immediatamente prima di passare attraverso la giunzione GE (asterisco bianco) <a href="https://www.jove.com/files/ftp_upload/52319/52319fig9highres.jpg" target="_blank">Clicca qui per vedere una versione più grande di questa figura.</a> <table border="0" cellpadding="0" cellspacing="0"><tbody><tr><td> PARAMETRI SWALLOW </td><td style="width:140px"> Alta Energy System </td><td style="width:140px"> Low Energy System </td></tr><tr><td> Inter-Rondine Interval (ISI) </td><td> X </td><td> X </td></tr><tr><td> Jaw Escursione Rate (Lick tasso equivalente) </td><td> X </td><td> X </td></tr><tr><td> Jaw Escursione Distanza </td><td> X </td><td> X </td></tr><tr><td> Lick-Rondine Rapporto </td><td> X </td><td> X </td></tr><tr><td> Rondine Tasso </td><td> X </td><td> X </td></tr><tr><td> PharyngEAL Tempo di transito (PTT) </td><td></td><td> X </td></tr><tr><td> Bolo velocità attraverso faringe </td><td></td><td> X </td></tr><tr><td> Esofagea Tempo di transito (ETT) </td><td></td><td> X </td></tr><tr><td> Bolo velocità attraverso Esofago </td><td></td><td> X </td></tr><tr><td> Bolo velocità attraverso faringe e dell&#39;esofago </td><td> X </td><td> X </td></tr><tr><td> Bolo Area </td><td></td><td> X </td></tr><tr><td> Faringea Residue Area </td><td></td><td> X </td></tr><tr><td> Volume di liquido Consumed </td><td> X </td><td> X </td></tr></tbody></table> Tabella 3: Rondine parametri quantificabili Utilizzando alta Versus Low Energy fluoroscopia Systems. Recentemente abbiamo ottenuto un sistema di fluoroscopia basso ingrandimento energetico chiamato The LabScope (Glenbrook Technologies, Randolph, NJ) che è stato specificamente progettato per il nostro laboratorio per l&#39;uso contopi e altri piccoli roditori (Figura 10). Tuttavia, i marcatamente maggiori livelli di ingrandimento di questo sistema reso impossibile vedere l&#39;intero meccanismo deglutizione di un topo in un unico campo di vista. Invece, due posizioni di prova sono richiesti, come mostrato in Figura 11. Posizione 1 consente la visualizzazione dell&#39;intera testa e prossimale regione toracica. Questa posizione è necessaria per valutare le fasi orale e faringea della deglutizione. Posizione 2 consente la visualizzazione dal punto di innesco rondine (cioè, vallecule) alla gastroesofageo (GE) giunzione. Questa posizione è necessaria per valutare la fase esofagea della deglutizione. Operazioni preliminari con il LabScope in combinazione con il nuovo protocollo VFSS murino ha identificato 13 parametri rondine oggettivi che sono costantemente quantificabile nei topi, che è quasi il doppio del numero ottenuto con alta energia (ad esempio, convenzionali) fluoroscopes (Tabella 3). Questo o<html> E SITO è attribuita alle capacità avanzate di ingrandimento Il LabScope, che consente la visualizzazione di numerose strutture anatomiche (Figura 12) che erano in sostanza invisibile quando si usano sistemi convenzionali: ad esempio, l&#39;osso ioide, trachea, e vertebre cervicali. Come risultato, siamo anche stati in grado di analizzare i video delle prove di penetrazione laringea e aspirazione. Né penetrazione né aspirazione è stato osservato per qualsiasi mouse in questo studio, indipendentemente dalle condizioni di salute o di malattia. <img alt="Figura 10" src="/files/ftp_upload/52319/52319fig10highres.jpg" width="650" /> Figura 10:. Il LabScope sinistra: Il LabScope esibisce come fluoroscopio desktop per piccoli animali. Destra: Vista del primo piano di The LabScope con componenti etichettati. La tabella forbice sta posizionando una camera di osservazione all&#39;interno del campo fluoroscopio visivo.<html> tp_upload / 52319 / 52319fig10highres.jpg &quot;target =&quot; _ blank &quot;&gt; Clicca qui per vedere una versione più grande di questa figura. <img alt="Figura 11" src="/files/ftp_upload/52319/52319fig11highres.jpg" width="650" /> Figura 11:. Low Energy fluoroscopia sistema Immagini di un topo ottenuta utilizzando un sistema di bassa fluoroscopia energetico. Si noti che la capacità alto ingrandimento impedisce visualizzazione dell&#39;intero meccanismo rondine all&#39;interno del campo di vista fluoroscopia. A sinistra: Posizione 1 - consente di visualizzare l&#39;intera testa e prossimale regione toracica. Il punto di innesco rondine (freccia nera) è essenzialmente centrato all&#39;interno del campo visivo. Destra: Posizione 2 - permette la visualizzazione dal punto di innesco rondine (freccia nera) fino al bivio di GE (asterisco bianco). Nota il bolo passa attraverso l&#39;esofago distale (freccia bianca).<html> g11highres.jpg &quot;target =&quot; _ blank &quot;&gt; Clicca qui per vedere una versione più grande di questa figura. <img alt="Figura 12" src="/files/ftp_upload/52319/52319fig12highres.jpg" width="650" /> Figura 12:. Usando strutture anatomiche visibile una fluoroscopia sistema energetico a basse anche con l&#39;impostazione di ingrandimento più basso (a sinistra), strutture ossee della testa e del collo di un mouse sono facilmente visibili utilizzando il nostro sistema di bassa fluoroscopia energia (cioè, il LabScope). Strutture anatomiche all&#39;interno del quadrato nero sono mostrati (ed etichettati) a più alto ingrandimento per la destra. Migliorata la visualizzazione delle strutture ossee consente la quantificazione di alcuni parametri aggiuntivi rondine che erano impossibili da analizzare con fluoroscopes alta energia. <a href="https://www.jove.com/files/ftp_upload/52319/52319fig12highres.jpg" target="_blank">Clicca qui per vedere una versione più grande di questa figura.</a> t &quot;&gt; Rondine rate e l&#39;intervallo tra rondine sono parametri VFSS rappresentativi che possono essere quantificate con sistema basse o alte fluoroscopia energia in combinazione con il nuovo protocollo VFSS murino Questi due parametri di rondine sono stati quantificati per tre gruppi di topi:. SOD1-G93A (SOD1) topi transgenici (cioè, un modello di SLA) in stadio terminale della malattia tra i 4-5 mesi di età, di età compresa tra i topi C57 (18-24 mesi di età), e un gruppo di controllo di soggetti sani giovani (4-8 mesi di età) topi C57 e fratellini nontransgenic dalla colonia SOD1. Tutti i dati si riferiscono a becco solo bere, utilizzando un sistema a bassa o ad alta energia fluoroscopia. Non sono state riscontrate differenze significative tra i giovani topi C57 e giovane nontransgenic (controllo) i topi dalla SOD1 colonia rispetto a questi due parametri, rondine. Pertanto, i dati sono stati combinati in un gruppo generale di &quot;controllo&quot; di giovani topi sani per il confronto con età compresa tra i topi C57 e topi SOD1 stadio terminale Rondine rate (ad esempio,il numero di rondini per 2 secondi consecutivi di bere ininterrotto) è stata significativamente più lenta per i topi SOD1 rispetto ai topi di età e controlli C57. Intervallo Inter-rondine (cioè il tempo che intercorre tra due rondini successivi) non era significativamente differente tra i due gruppi. Questi risultati supportano l&#39;idea che i profili disfagia sono suscettibili di essere nettamente diverso per ogni condizione di malattia (Figura 13). <img alt="Figura 13" src="/files/ftp_upload/52319/52319fig13highres.jpg" width="650" /> Figura 13:. I risultati preliminari Questa figura mostra i risultati preliminari rappresentativi per due parametri di rondine VFSS quantificati utilizzando il protocollo VFSS murino: ingoiare rate (a sinistra) e l&#39;intervallo inter-rondine (a destra). Rondine tasso era significativamente più lenta per i topi SOD1 rispetto ai topi di età e controlli C57. Non significative differenze di gruppo sono stati identificati per inter-rondine traval. Le linee nella parte superiore delle barre indicano differenze statisticamente significative (p &lt;0.05) tra i gruppi, identificati utilizzando Bonferroni confronti a coppie. Barre di errore rappresentano ± 1 SEM. <a href="https://www.jove.com/files/ftp_upload/52319/52319fig13highres.jpg" target="_blank">Cliccate qui per vedere una versione più grande di questa figura.</a>

Watch this Scientific Journal Video about Adapting Human Videofluoroscopic Swallow Study Methods to Detect and Characterize Dysphagia in Murine Disease Models at JoVE.com

Adapting Human Videofluoroscopic Swallow Study Methods to Detect and Characterize Dysphagia in Murine Disease Models

Questo studio adattato con successo videofluoroscopia deglutizione studio (VFSS) metodi umani per l&#39;utilizzo con modelli di malattia murini al fine di facilitare la ricerca traslazionale disfagia.

Adattamento umani videofluoroscopia Rondine metodi di studio per individuare e caratterizzare disfagia in modelli di malattia Murine

This study adapted human videofluoroscopic swallowing study (VFSS) methods for use with murine disease models for the purpose of facilitating ...

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21.2K Views.  University of Missouri.  Questo studio adattato con successo videofluoroscopia deglutizione studio (VFSS) metodi umani per l'utilizzo con modelli di malattia murini al fine di facilitare la ricerca traslazionale disfagia. 

Video: Adapting Human Videofluoroscopic Swallow Study Methods to Detect and Characterize Dysphagia in Murine Disease Models

Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, recovery from SCI typically involves long term rehabilitation. While recovery of walking ability is a primary goal in many patients early after injury, those with a motor incomplete SCI, indicating partial preservation of volitional control, may have the sufficient residual descending pathways necessary to attain this goal. However, despite physical interventions, motor impairments including weakness, and the manifestation of abnormal involuntary reflex activity, called spasticity or spasms, are thought to contribute to reduced walking recovery. Doctrinaire thought suggests that remediation of this abnormal motor reflexes associated with SCI will produce functional benefits to the patient. For example, physicians and therapists will provide specific pharmacological or physical interventions directed towards reducing spasticity or spasms, although there continues to be little empirical data suggesting that these strategies improve walking ability.
In the past few decades, accumulating data has suggested that specific neuromodulatory agents, including agents which mimic or facilitate the actions of the monoamines, including serotonin (5HT) and norepinephrine (NE), can initiate or augment walking behaviors in animal models of SCI. Interestingly, many of these agents, particularly 5HTergic agonists, can markedly increase spinal excitability, which in turn also increases reflex activity in these animals. Counterintuitive to traditional theories of recovery following human SCI, the empirical evidence from basic science experiments suggest that this reflex hyper excitability and generation of locomotor behaviors are driven in parallel by neuromodulatory inputs (5HT) and may be necessary for functional recovery following SCI. 
The application of this novel concept derived from basic scientific studies to promote recovery following human SCI would appear to be seamless, although the direct translation of the findings can be extremely challenging. Specifically, in the animal models, an implanted catheter facilitates delivery of very specific 5HT agonist compounds directly onto the spinal circuitry. The translation of this technique to humans is hindered by the lack of specific surgical techniques or available pharmacological agents directed towards 5HT receptor subtypes that are safe and effective for human clinical trials. However, oral administration of commonly available 5HTergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may be a viable option to increase central 5HT concentrations in order to facilitate walking recovery in humans. Systematic quantification of how these SSRIs modulate human motor behaviors following SCI, with a specific focus on strength, reflexes, and the recovery of walking ability, are missing.
This video demonstration is a progressive attempt to systematically and quantitatively assess the modulation of reflex activity, volitional strength and ambulation following the acute oral administration of an SSRI in human SCI. Agents are applied on single days to assess the immediate effects on motor function in this patient population, with long-term studies involving repeated drug administration combined with intensive physical interventions.

This video demonstrates modulation of reflex activity, volitional strength and ambulation through clinical and quantitative assessments in individuals with motor incomplete SCI as a result of acute oral administration of a serotonin reuptake inhibitor (SSRI).

I metodi per quantificare alterazioni indotta farmacologicamente in funzione motoria in Human incompleta SCI

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, ...

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Medicina

Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain

The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform PrPSc 1. PrPC is detergent-soluble and sensitive to proteinase K (PK)-digestion, whereas PrPSc forms detergent-insoluble aggregates and is partially resistant to PK2-6. The conversion of PrPC to PrPSc is known to involve a conformational transition of &alpha;-helical to &beta;-sheet structures of the protein. However, the in vivo pathway is still poorly understood. A tentative endogenous PrPSc, intermediate PrP* or "silent prion", has yet to be identified in the uninfected brain7.
Using a combination of biophysical and biochemical approaches, we identified insoluble PrPC aggregates (designated iPrPC) from uninfected mammalian brains and cultured neuronal cells8, 9. Here, we describe detailed procedures of these methods, including ultracentrifugation in detergent buffer, sucrose step gradient sedimentation, size exclusion chromatography, iPrP enrichment by gene 5 protein (g5p) that specifically bind to structurally altered PrP forms10, and PK-treatment. The combination of these approaches isolates not only insoluble PrPSc and PrPC aggregates but also soluble PrPC oligomers from the normal human brain. Since the protocols described here have been used to isolate both PrPSc from infected brains and iPrPC from uninfected brains, they provide us with an opportunity to compare differences in physicochemical features, neurotoxicity, and infectivity between the two isoforms. Such a study will greatly improve our understanding of the infectious proteinaceous pathogens. The physiology and pathophysiology of iPrPC are unclear at present. Notably, in a newly-identified human prion disease termed variably protease-sensitive prionopathy, we found a new PrPSc that shares the immunoreactive behavior and fragmentation with iPrPC 11, 12. Moreover, we recently demonstrated that iPrPC is the main species that interacts with amyloid-&beta; protein in Alzheimer disease13. In the same study, these methods were used to isolate Abeta aggregates and oligomers in Alzheimer's disease13, suggesting their application to non-prion protein aggregates involved in other neurodegenerative disorders.

A new species of cellular prion protein (PrPC) has recently been identified in uninfected human brains using the methods described here. These methods can be used to isolate various PrP species, while some of them are also useful in isolating other misfolded protein aggregates from human brains.

Isolamento di oligomeri PrP solubili e insolubili nel cervello umano normale

The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform ...

Spectral Karyotyping to Study Chromosome Abnormalities in Humans and Mice with Polycystic Kidney Disease

Conventional method to identify and classify individual chromosomes depends on the unique banding pattern of each chromosome in a specific species being analyzed 1, 2. This classical banding technique, however, is not reliable in identifying complex chromosomal aberrations such as those associated with cancer. To overcome the limitations of the banding technique, Spectral Karyotyping (SKY) is introduced to provide much reliable information on chromosome abnormalities.
SKY is a multicolor fluorescence in-situ hybridization (FISH) technique to detect metaphase chromosomes with spectral microscope 3, 4. SKY has been proven to be a valuable tool for the cytogenetic analysis of a broad range of chromosome abnormalities associated with a large number of genetic diseases and malignancies 5, 6. SKY involves the use of multicolor fluorescently-labelled DNA probes prepared from the degenerate oligonucleotide primers by PCR. Thus, every chromosome has a unique spectral color after in-situ hybridization with probes, which are differentially labelled with a mixture of fluorescent dyes (Rhodamine, Texas Red, Cy5, FITC and Cy5.5). The probes used for SKY consist of up to 55 chromosome specific probes 7-10.
The procedure for SKY involves several steps (Figure 1). SKY requires the availability of cells with high mitotic index from normal or diseased tissue or blood. The chromosomes of a single cell from either a freshly isolated primary cell or a cell line are spread on a glass slide. This chromosome spread is labeled with a different combination of fluorescent dyes specific for each chromosome. For probe detection and image acquisition,the spectral imaging system consists of sagnac interferometer and a CCD camera. This allows measurement of the visible light spectrum emitted from the sample and to acquire a spectral image from individual chromosomes. HiSKY, the software used to analyze the results of the captured images, provides an easy identification of chromosome anomalies. The end result is a metaphase and a karyotype classification image, in which each pair of chromosomes has a distinct color (Figure 2). This allows easy identification of chromosome identities and translocations. For more details, please visit Applied Spectral Imaging website (<a href="http://www.spectral-imaging.com/" target="_blank">http://www.spectral-imaging.com/</a>).
SKY was recently used for an identification of chromosome segregation defects and chromosome abnormalities in humans and mice with Autosomal Dominant Polycystic Kidney Disease (ADPKD), a genetic disease characterized by dysfunction in primary cilia 11-13. Using this technique, we demonstrated the presence of abnormal chromosome segregation and chromosomal defects in ADPKD patients and mouse models 14. Further analyses using SKY not only allowed us to identify chromosomal number and identity, but also to accurately detect very complex chromosomal aberrations such as chromosome deletions and translocations (Figure 2).

Spectral Karyotyping (SKY) is an advanced cytogenetics technique to identify genomic and chromosomal aberrations. This technique takes advantage of chromosome painting probes, which allow classification of all chromosomes. SKY can also identify complex chromosome aberrations and segregation defects in mice and humans with various diseases, including polycystic kidney disease.

Cariotipo spettrale allo studio anomalie cromosomiche negli esseri umani e nei topi con malattia del rene policistico

Conventional method to identify and classify individual chromosomes depends on the unique banding pattern of each chromosome in a specific species being ...

Coordinate Mapping of Hyolaryngeal Mechanics in Swallowing

Characterizing hyolaryngeal movement is important to dysphagia research. Prior methods require multiple measurements to obtain one kinematic measurement whereas coordinate mapping of hyolaryngeal mechanics using Modified Barium Swallow (MBS) uses one set of coordinates to calculate multiple variables of interest. For demonstration purposes, ten kinematic measurements were generated from one set of coordinates to determine differences in swallowing two different bolus types. Calculations of hyoid excursion against the vertebrae and mandible are correlated to determine the importance of axes of reference.
To demonstrate coordinate mapping methodology, 40 MBS studies were randomly selected from a dataset of healthy normal subjects with no known swallowing impairment. A 5 ml thin-liquid bolus and a 5 ml pudding swallows were measured from each subject. Nine coordinates, mapping the cranial base, mandible, vertebrae and elements of the hyolaryngeal complex, were recorded at the frames of minimum and maximum hyolaryngeal excursion. Coordinates were mathematically converted into ten variables of hyolaryngeal mechanics.
Inter-rater reliability was evaluated by Intraclass correlation coefficients (ICC). Two-tailed t-tests were used to evaluate differences in kinematics by bolus viscosity. Hyoid excursion measurements against different axes of reference were correlated. Inter-rater reliability among six raters for the 18 coordinates ranged from ICC = 0.90 - 0.97. A slate of ten kinematic measurements was compared by subject between the six raters. One outlier was rejected, and the mean of the remaining reliability scores was ICC = 0.91, 0.84 - 0.96, 95% CI. Two-tailed t-tests with Bonferroni corrections comparing ten kinematic variables (5 ml thin-liquid vs. 5 ml pudding swallows) showed statistically significant differences in hyoid excursion, superior laryngeal movement, and pharyngeal shortening (p &#60; 0.005). Pearson correlations of hyoid excursion measurements from two different axes of reference were: r = 0.62, r2 = 0.38, (thin-liquid); r = 0.52, r2 = 0.27, (pudding).
Obtaining landmark coordinates is a reliable method to generate multiple kinematic variables from video fluoroscopic images useful in dysphagia research.

Coordinate mapping is a method of documenting salient features of hyolaryngeal biomechanics in the pharyngeal phase of swallowing. This methodology uses image analysis software to record coordinates of anatomical landmarks. These coordinates are imported into an excel macro and translated into kinematic variables of interest useful in dysphagia research.

Coordinare mappatura dei Hyolaryngeal Meccanica di deglutizione

Characterizing hyolaryngeal movement is important to dysphagia research. Prior methods require multiple measurements to obtain one kinematic measurement ...

Murine Endoscopy for In Vivo Multimodal Imaging of Carcinogenesis and Assessment of Intestinal Wound Healing and Inflammation

Mouse models are widely used to study pathogenesis of human diseases and to evaluate diagnostic procedures as well as therapeutic interventions preclinically. However, valid assessment of pathological alterations often requires histological analysis, and when performed ex vivo, necessitates death of the animal. Therefore in conventional experimental settings, intra-individual follow-up examinations are rarely possible. Thus, development of murine endoscopy in live mice enables investigators for the first time to both directly visualize the gastrointestinal mucosa and also repeat the procedure to monitor for alterations. Numerous applications for in vivo murine endoscopy exist, including studying intestinal inflammation or wound healing, obtaining mucosal biopsies repeatedly, and to locally administer diagnostic or therapeutic agents using miniature injection catheters. Most recently, molecular imaging has extended diagnostic imaging modalities allowing specific detection of distinct target molecules using specific photoprobes. In conclusion, murine endoscopy has emerged as a novel cutting-edge technology for diagnostic experimental in vivo imaging and may significantly impact on preclinical research in various fields.

Murine Endoscopy for In Vivo Multimodal Imaging of Carcinogenesis and Assessment of Intestinal Wound Healing and Inflammation

Small animal imaging techniques allow serial diagnostic examinations and therapeutic interventions in vivo. Recently, the scope of applications has significantly widened and currently includes assessment of colonic tumor development, wound healing and monitoring of inflammation. This protocol illustrates these diverse potential applications of murine endoscopy.

Murino Endoscopia per<em&gt; In Vivo</em&gt; Guarigione Imaging Multimodale di Cancerogenesi e valutazione della ferita intestinale e infiammazione

Mouse models are widely used to study pathogenesis of human diseases and to evaluate diagnostic procedures as well as therapeutic interventions ...

<meta charset="utf8"></head><body>Riduzione dello stress degli animali da ricerca con la somministrazione di farmaci guidata da micropipette

Use of Micropipette-Guided Drug Administration as an Alternative Method to Oral Gavage in Rodent Models

Oral gavage (OG) with the use of a cannula attached to a syringe is one of the most common methods used to deliver precise dosing of compounds to the stomach of research animals. Unfortunately, this method comes with difficulties for both the operator and the research animal. Studies have shown that OG may lead to complications, including esophagitis, perforation of the esophagus, and inadvertent tracheal drug administration. In addition, OG is associated with increased plasma and fecal corticosterone levels (due to stress), altered blood pressure, and increased heart rate, which could negatively influence or bias study results. A previously developed alternative method termed micropipette-guided drug administration (MDA) incentivizes the animal to consume treatments readily in a minimally invasive manner. Herein, we present examples of the use of the MDA technique with treatments reconstituted in different vehicles and demonstrate effective delivery of the varied treatments to multiple different mouse strains. We further demonstrate that MDA is a technique that decreases the timing and invasiveness of drug administration and does not affect the gut microbiome composition as assessed by quantitative analysis of core gut microbial species. Overall, MDA may offer a less stressful and effective alternative to OG.

<meta charset="utf8"></head><body>Uso della somministrazione di farmaci guidata da micropipette come metodo alternativo alla sonda gastrica orale nei modelli di roditori

Here, we describe micropipette-guided drug administration (MDA) as an alternative method to oral gavage that incentivizes the research animal to ingest treatments readily with minimal stress and discomfort.

Uso della somministrazione di farmaci guidata da micropipette come metodo alternativo alla sonda gastrica orale nei modelli di roditori

Oral gavage (OG) with the use of a cannula attached to a syringe is one of the most common methods used to deliver precise dosing of compounds to the ...

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In Vivo Evaluation of the Mechanical and Viscoelastic Properties of the Rat Tongue

The tongue is a highly innervated and vascularized muscle hydrostat on the floor of the mouth of most vertebrates. Its primary functions include supporting mastication and deglutition, as well as taste-sensing and phonetics. Accordingly, the strength and volume of the tongue can impact the ability of vertebrates to accomplish basic activities such as feeding, communicating, and breathing. Human patients with sleep apnea have enlarged tongues, characterized by reduced muscle tone and increased intramuscular fat that can be visualized and quantified by magnetic resonance imaging (MRI). The abilities to measure force generation and viscoelastic properties of the tongue constitute important tools for obtaining functional information to correlate with imaging data. Here, we present techniques for measuring tongue force production in anesthetized Zucker rats via electrical stimulation of the hypoglossal nerves and for determining the viscoelastic properties of the tongue by applying passive Lissajous force/deformation curves.

In Vivo Evaluation of the Mechanical and Viscoelastic Properties of the Rat Tongue

We describe a surgical procedure in an anesthetized rat model for determining the muscle tone and viscoelastic properties of the tongue. The procedure involves specific stimulation of the hypoglossal nerves and application of passive Lissajous force/deformation curves to the muscle.

Valutazione in vivo delle proprietà meccaniche e viscoelastiche del linguaggio del ratto

The tongue is a highly innervated and vascularized muscle hydrostat on the floor of the mouth of most vertebrates. Its primary functions include ...

&#181;Tongue: A Microfluidics-Based Functional Imaging Platform for the Tongue In Vivo

Intravital fluorescence microscopy is a tool used widely to study multicellular dynamics in a live animal. However, it has not been successfully used in the taste sensory organ. By integrating microfluidics into the intravital tongue imaging window, the &#181;Tongue provides reliable functional images of taste cells in vivo under controlled exposure to multiple tastants. In this paper, a detailed step-by-step procedure to utilize the &#181;Tongue system is presented. There are five subsections: preparing of tastant solutions, setting up of a microfluidic module, sample mounting, acquiring functional image data, and data analysis. Some tips and techniques to solve the practical issues that may arise when using the &#181;Tongue are also presented.

 &#181;Tongue: A Microfluidics-Based Functional Imaging Platform for the Tongue In Vivo

The article introduces the &#181;Tongue (microfluidics-on-a-tongue) device for functional taste cell imaging in vivo by integrating microfluidics into an intravital imaging window on the tongue.

μTongue: una piattaforma di imaging funzionale basata sulla microfluidica per la lingua in vivo

Intravital fluorescence microscopy is a tool used widely to study multicellular dynamics in a live animal. However, it has not been successfully used in ...

Adattamento umani videofluoroscopia Rondine metodi di studio per individuare e caratterizzare disfagia in modelli di malattia Murine

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Esplora Altri Video

I metodi per quantificare alterazioni indotta farmacologicamente in funzione motoria in Human incompleta SCI

Isolamento di oligomeri PrP solubili e insolubili nel cervello umano normale

Cariotipo spettrale allo studio anomalie cromosomiche negli esseri umani e nei topi con malattia del rene policistico

Coordinare mappatura dei Hyolaryngeal Meccanica di deglutizione

Murino Endoscopia per

Uso della somministrazione di farmaci guidata da micropipette come metodo alternativo alla sonda gastrica orale nei modelli di roditori

Uso della somministrazione di farmaci guidata da micropipette come metodo alternativo alla sonda gastrica orale nei modelli di roditori

Uso della somministrazione di farmaci guidata da micropipette come metodo alternativo alla sonda gastrica orale nei modelli di roditori

Valutazione in vivo delle proprietà meccaniche e viscoelastiche del linguaggio del ratto

μTongue: una piattaforma di imaging funzionale basata sulla microfluidica per la lingua in vivo