testing-efficacy-pharmacological-agents-pericardial-target-delivery

Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, ...

Rice University

Cisplatin, a cancer chemotherapy agent, like many toxins, produces emesis and nausea. Abdominal vagotomy, or treatment with 5-HT3 receptor antagonists, blocks cisplatin-induced emesis, which suggests that it produces (albeit indirectly) activation of 5-HT3 receptors on vagal afferent fibers. Cisplatin induces a large release of intestinal 5-hydroxytryptamine (5-HT) that enters the hepatic portal vein, which may activate vagal afferent fibers in the portal vein or liver to induce emesis or other side effects of treatment (e.g., reduced food intake). This study was conducted to assess the effects of cisplatin on gastrointestinal and portal vein/liver vagal afferent fibers by recording the neurophysiological responses of the common hepatic branch (CHB) of the vagus in the rat. The CHB contains vagal afferent fibers that innervate the gastrointestinal (GI) tract, portal vein, and liver. Cisplatin (10 mg/kg; jugular vein, j.v.) produced an increase in multi-unit CHB activity and this effect was blocked by a 5-HT3-receptor antagonist (Y-25130, 0.8 mg, j.v.). Cutting the gastroduodenal branch (GDB), a sub-branch of the CHB that contains GI afferent fibers, resulted in a complete suppression of the multi-unit CHB discharge produced by cisplatin treatment. Single units that were cisplatin sensitive had their activity reduced by either 5-HT3 receptor antagonist treatment or cutting the GDB. Conversely, cisplatin insensitive units were not affected by 5-HT3-antagonism or GDB ablation. The present results indicate that cisplatin activates GI vagal afferent fibers via 5-HT3 receptors but does not affect portal vein/liver vagal afferent fibers, which indicates that intestinal but not hepatic afferent fibers are involved in the toxic effects of cisplatin.

Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin.

Pluronic P105 micelles are potential candidates as chemotherapy drug delivery vehicles using ultrasonic stimulation as a release trigger. Acoustic power has been previously shown to release two anthracycline agents from these polymeric carriers. In this study, an ultrasonic exposure chamber with fluorescence detection was used to examine the mechanism of doxorubicin release from P105 micelles. Acoustic spectra were collected and analyzed, at the same spatial position as fluorescence data, to probe the role of cavitation in drug release. Our study showed a strong correlation between percent drug release and subharmonic acoustic emissions, and we attribute the drug release to collapse cavitation that perturbs the structure of the micelle and releases drug.

The role of cavitation in acoustically activated drug delivery.

Sonication is a simple method for reducing the size of liposomes. We report the size distributions of liposomes as a function of sonication time using three different techniques. Liposomes, mildly sonicated for just 30 sec, had bimodal distributions when surface-weighted with modes at about 140 and 750 nm. With extended sonication, the size distribution remains bimodal but the average diameter of each population decreases and the smaller population becomes more numerous. Independent measurements of liposome size using Dynamic Light Scattering (DLS), transmission electron microscopy (TEM), and the nystatin/ergosterol fusion assay all gave consistent results. The bimodal distribution (even when number-weighted) differs from the Weibull distribution commonly observed for liposomes sonicated at high powers over long periods of time and suggests that a different mechanism may be involved in mild sonication. The observations are consistent with the following mechanism for decreasing liposome size. During ultrasonic irradiation, cavitation, caused by oscillating microbubbles, produces shear fields. Large liposomes that enter these fields form long tube-like appendages that can pinch-off into smaller liposomes. This proposed mechanism is consistent with colloidal theory and the observed behavior of liposomes in shear fields.

Reducing liposome size with ultrasound: bimodal size distributions.

Liposome size is a vital parameter of many quantitative biophysical studies. Sonication, or exposure to ultrasound, is used widely to manufacture artificial liposomes, yet little is known about the mechanism by which liposomes are affected by ultrasound. Cavitation, or the oscillation of small gas bubbles in a pressure-varying field, has been shown to be responsible for many biophysical effects of ultrasound on cells. In this study, we correlate the presence and type of cavitation with a decrease in liposome size. Aqueous lipid suspensions surrounding a hydrophone were exposed to various intensities of ultrasound and hydrostatic pressures before measuring their size distribution with dynamic light scattering. As expected, increasing ultrasound intensity at atmospheric pressure decreased the average liposome diameter. The presence of collapse cavitation was manifested in the acoustic spectrum at high ultrasonic intensities. Increasing hydrostatic pressure was shown to inhibit the presence of collapse cavitation. Collapse cavitation, however, did not correlate with decreases in liposome size, as changes in size still occurred when collapse cavitation was inhibited either by lowering ultrasound intensity or by increasing static pressure. We propose a mechanism whereby stable cavitation, another type of cavitation present in sound fields, causes fluid shearing of liposomes and reduction of liposome size. A mathematical model was developed based on the Rayleigh-Plesset equation of bubble dynamics and principles of acoustic microstreaming to estimate the shear field magnitude around an oscillating bubble. This model predicts the ultrasound intensities and pressures needed to create shear fields sufficient to cause liposome size change, and correlates well with our experimental data.

The role of cavitation in liposome formation.

Basic and clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) decrease fatal arrhythmias and infarct sizes. This study investigated if pericardial delivery of n-3 PUFAs would protect the myocardium from ischemic damages and arrhythmias. Acute myocardial infarctions were induced in 23 pigs with either 45 min balloon inflations or clamp occlusions of the left anterior descending coronary arteries and 180 min reperfusion. Docosahexaenoic acid (C22:6n-3, DHA, 45 mg), one of the main n-3 PUFAs in fish oil, was infused within the pericardial space only during the 40-min stabilizing phase, 45 min ischemia and initial 5 min reperfusion. Hemodynamics and cardiac functions were very similar between the DHA-treated and control groups. However, DHA therapy significantly reduced infarct sizes from 56.8 +/- 4.9% for controls (n = 12) to 28.8 +/- 7.9% (P < 0.01) for DHA-treated animals (n = 11). Compared with controls, DHA-treated animals significantly decreased heart rates and reduced ventricular arrhythmia scores during ischemia. Furthermore, three (25%) control animals experienced eight episodes of ventricular fibrillation (VF), and two died subsequent to unsuccessful defibrillation. In contrast, only 1 (9%) of 11 DHA-treated pigs elicited one episode of VF that was successfully converted via defibrillation to normal rhythm; thus, mortality was reduced from 17% in the controls to 0% in the DHA-treated animals. These data demonstrate that pericardial infusion of n-3 PUFA DHA can significantly reduce both malignant arrhythmias and infarct sizes in a porcine infarct model. Pericardial administration of n-3 PUFAs could represent a novel approach to treating or preventing myocardial infarctions.

Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias.

Base et cliniques sugg&egrave;rent que les om&eacute;ga-3 (n-3) d&#39;acides gras polyinsatur&eacute;s (AGPI) diminuent arythmies mortelles et la taille de l&#39;infarctus. Cette &eacute;tude examine si livraison p&eacute;ricardique des AGPI n-3 prot&eacute;geraient le myocarde des arythmies et des dommages isch&eacute;miques. Infarctus du myocarde aigus ont &eacute;t&eacute; induites chez 23 porcs avec inflations ballon 45 min ou pince les occlusions des art&egrave;res descendantes ant&eacute;rieures gauche et 180 min de reperfusion. L&#39;acide docosahexano&iuml;que (C22-3, DHA, 45 mg), un des principaux AGPI n-3 en huile de poisson, a &eacute;t&eacute; perfus&eacute; dans l&#39;espace p&eacute;ricardique seulement pendant la phase de stabilisation 40 min, 45 min d&#39;isch&eacute;mie et de reperfusion initiale 5 min. Fonctions h&eacute;modynamique et cardiaque sont tr&egrave;s semblables entre le DHA impr&eacute;gn&eacute;es et le groupe t&eacute;moin. Cependant, th&eacute;rapie DHA a sensiblement diminu&eacute; tailles infarctus de 56,8 +/-4,9 % chez les t&eacute;moins (n = 12) &agrave; 28,8 +/-7,9 % (P &lt; 0,01) pour les animaux trait&eacute;s DHA (n = 11). Comparativement aux t&eacute;moins, chez les animaux trait&eacute;s DHA significativement diminu&eacute; les fr&eacute;quences cardiaques et r&eacute;duit les scores d&#39;arythmie ventriculaire au cours de l&#39;isch&eacute;mie. En outre, trois animaux de contr&ocirc;le (25 %) a connu huit &eacute;pisodes de fibrillation ventriculaire (FV) et deux sont morts &agrave; la suite de d&eacute;fibrillation infructueuse. En revanche, seulement 1 (9 %) des 11 porcs impr&eacute;gn&eacute;es de DHA a suscit&eacute; un &eacute;pisode de la VF qui a &eacute;t&eacute; convertie avec succ&egrave;s par l&#39;interm&eacute;diaire de d&eacute;fibrillation &agrave; rythme normal ; ainsi, la mortalit&eacute; a &eacute;t&eacute; r&eacute;duite de 17 % chez les t&eacute;moins &agrave; 0 % chez les animaux trait&eacute;s DHA. Ces r&eacute;sultats d&eacute;montrent que p&eacute;ricardique infusion de n-3 PUFA DHA peut r&eacute;duire consid&eacute;rablement les arythmies malignes et tailles d&#39;infarctus dans un mod&egrave;le porcin infarctus. P&eacute;ricardique administration des AGPI n-3 pourrait repr&eacute;senter une nouvelle approche pour traiter ou pr&eacute;venir l&#39;infarctus du myocarde.

P&eacute;ricardique livraison d&#39;acide gras om&eacute;ga-3: une nouvelle approche pour r&eacute;duire la taille de l&#39;infarctus du myocarde et des arythmies.

Base e clinici suggeriscono che omega-3 (n-3) acidi grassi polinsaturi (PUFA) diminuire fatali aritmie e infarto dimensioni. Questo studio ha studiato se pericardico consegna di n-3 PUFA sarebbe proteggere il miocardio da aritmie e danni ischemici. Infarti del miocardio acuti sono stati indotti in 23 suini con inflazioni palloncino 45 min o morsetto occlusioni delle arterie coronarie sinistra discendente anteriore e 180 min di riperfusione. Acido docosaesaenoico (C22:6n-3, DHA, 45 mg), uno del principale n-3 PUFA in olio di pesce, &egrave; stato infuso all&#39;interno dello spazio pericardico solo nella fase stabilizzante 40 min, 45 min di ischemia e riperfusione iniziale 5 min. Emodinamica e cardiaco funzioni erano molto simili tra i trattati con DHA e gruppi di controllo. Tuttavia, la terapia DHA notevolmente ridotto dimensioni infarto da 56.8 + 4,9% per i controlli (n = 12) a 28,8 + 7,9% (P &lt; 0,01) per gli animali trattati con DHA (n = 11). Rispetto ai controlli, gli animali trattati con DHA significativamente diminuiti tassi di cuore e ridotto il gol di aritmia ventricolare durante l&#39;ischemia. Inoltre, tre animali di controllo (25%) sperimentato otto episodi di fibrillazione ventricolare (VF) e due morirono successivamente defibrillazione infruttuosa. In contrasto, solo 1 (9%) di 11 suini trattati con DHA ha suscitato un episodio di VF che &egrave; stato convertito correttamente tramite defibrillazione a ritmo normale, cos&igrave;, la mortalit&agrave; &egrave; stato ridotto da 17% nei controlli a 0% negli animali trattati con DHA. Questi dati dimostrano che l&#39;infusione pericardico di n-3 PUFA DHA pu&ograve; ridurre significativamente entrambi aritmie maligne e dimensioni di infarto in un modello di infarct suina. Pericardico somministrazione di n-3 PUFA potrebbe rappresentare un romanzo approccio per trattare o prevenire infarti del miocardio.

Pericardico consegna di acidi grassi omega-3: un nuovo approccio per ridurre le dimensioni di infarto miocardico e aritmie.

B&aacute;sica y cl&iacute;nica de la evidencia sugiere que los &aacute;cidos grasos poliinsaturados (AGPI) omega-3 (n-3) disminuir las arritmias fatales y tama&ntilde;os de infarto. Este estudio investig&oacute; si entrega pericardial de PUFAs n-3 proteger&iacute;a el miocardio de arritmias y da&ntilde;o isqu&eacute;mico. Infartos agudos de miocardio fueron inducidos en 23 cerdos con inflaciones de globo de 45 minutos o abrazadera obstrucciones de las arterias de coronaria descendentes anteriores izquierdas y 180 min reperfusi&oacute;n. &Aacute;cido docosahexaenoico (C22:6n-3, DHA, 45 mg), uno de los principales PUFAs n-3 en el aceite de pescado, fue infundida en el espacio peric&aacute;rdico s&oacute;lo durante la fase de estabilizaci&oacute;n de 40 min, 45 minutos de isquemia y reperfusi&oacute;n inicial 5 min. Las funciones card&iacute;aca y hemodin&aacute;mica eran muy similares entre los tratados con DHA y grupos de control. Sin embargo, DHA tratamiento redujo significativamente los tama&ntilde;os de infarto de 56.8 +/-4.9% para los controles (n = 12) a 28.8 + /-7,9% (P 0.01 &lt;) para animales tratados con DHA (n = 11). En comparaci&oacute;n con controles, animales tratados con DHA significativamente disminuci&oacute;n el ritmo cardiaco y reducci&oacute;n decenas de arritmia ventricular durante la isquemia. Adem&aacute;s, tres animales de control (25%) experimentaron ocho episodios de fibrilaci&oacute;n ventricular (FV) y dos murieron despu&eacute;s de fracasada desfibrilaci&oacute;n. Por el contrario, s&oacute;lo 1 (9%) de 11 cerdos tratados con DHA produce un episodio de FV que se convierte con &eacute;xito a trav&eacute;s de desfibrilaci&oacute;n a ritmo normal, por lo tanto, la mortalidad se redujo de 17% en los controles a 0% en los animales tratados con DHA. Estos datos demuestran que la infusi&oacute;n pericardial de DHA de PUFA n-3 puede reducir significativamente arritmias malignas y tama&ntilde;os de infarto en un modelo porcino de infarto. Peric&aacute;rdica administraci&oacute;n de AGPI n-3 podr&iacute;a representar una novela acercarse para tratar o prevenir los infartos del miocardio.

Peric&aacute;rdico entrega de &aacute;cido graso omega-3: un nuevo enfoque para reducir el tama&ntilde;o del infarto de miocardio y arritmias.

Ultrasound (US) is used to enhance and target delivery of drugs and genes to cancer tissues. The present study further examines the role of acoustic cavitation in US-induced permeabilization of cell membranes and subsequent drug or gene uptake by the cell. Rat colon cancer cells were exposed to ultrasound at various static pressures to examine the hypothesis that oscillating bubbles, also known as cavitating bubbles, permeabilize cells. Increasing pressure suppresses bubble cavitation activity; thus, if applied pressure were to reduce drug uptake, cell permeabilization would be strongly linked to bubble cavitation activity. Cells were exposed to 476 kHz pulsed ultrasound at average intensities of 2.75 W/cm(2) and 5.5 W/cm(2) at various pressures and times in an isothermal chamber. Cell fractions with reversible membrane damage (calcein uptake) and irreversible damage (propidium iodide uptake) were analyzed by flow cytometry. Pressurization to 3 atm nearly eliminated the biological effect of US in promoting calcein uptake. Data also showed a linear increase in membrane permeability with respect to insonation time and intensity. This research shows that US-mediated cell membrane permeability is likely linked to cavitation bubble activity.

Over-pressure suppresses ultrasonic-induced drug uptake.

No todas las bombillas de aspiraci&oacute;n cerrado de drenaje son equivalentes, y puede haber una discrepancia entre la supuesta y observada la eficacia cl&iacute;nica. Se evaluaron cuatro popular bulbo aspiraci&oacute;n estom&aacute;ticos para comparar directamente su m&aacute;ximo alcanzable recogidos de volumen m&aacute;ximo, de succi&oacute;n y presi&oacute;n negativa que se mantuvo en relaci&oacute;n con el volumen recoge.

No cada bulbo es una rosa: una comparaci&oacute;n funcional de dispositivos de succi&oacute;n del bulbo.

Not all closed drainage suction bulbs are equivalent, and there may be a discrepancy between purported and observed clinical efficacy. We evaluated four popular bulb suction apparati to directly compare their maximum attainable suction, maximum volume collected, and negative pressure maintained relative to volume collected.

Not every bulb is a rose: a functional comparison of bulb suction devices.

Pas toutes les ampoules d&#39;aspiration de drainage ferm&eacute; sont &eacute;quivalents, et il peut y avoir un &eacute;cart entre la pr&eacute;tendue efficacit&eacute; clinique observ&eacute;e. Nous avons &eacute;valu&eacute; quatre appareils d&#39;aspiration de l&#39;ampoule populaires pour comparer directement leur maximum atteignable volume d&#39;aspiration, maximum pr&eacute;lev&eacute; et d&eacute;pression maintenue par rapport au volume collect&eacute;.

Non chaque ampoule est une rose : une comparaison fonctionnelle des dispositifs d&#39;aspiration de l&#39;ampoule.

Non tutte le lampadine di aspirazione di drenaggio chiuso sono equivalenti, e ci pu&ograve; essere una discrepanza tra osservato e presunta efficacia clinica. Abbiamo valutato quattro apparati di aspirazione popolare lampadina per confrontare direttamente il valore massimo raggiungibile, aspirazione, massimo volume raccolto e pressione negativa mantenuto relativo volume raccolto.

Non ogni lampadina &egrave; una rosa: un confronto funzionale dei dispositivi di aspirazione del bulbo.

Stimulus overload 'video game epilepsy' causes seizures in young and old.

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. It has been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis. We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whether hHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-time RT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4 current (I(h)) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and action potential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced I(h) and shifted activation in the depolarizing direction, thus modifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed that HCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder. Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that I(h) exhibits voltage-dependent hysteresis behavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.

Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking.

L&#39;hyperpolarisation cycliques nucl&eacute;otide-d&eacute;pendants (HCN) canaux modulent et r&eacute;gulent les taux et le rythme cardiaque. Il a &eacute;t&eacute; sugg&eacute;r&eacute; que, contrairement aux HCN1 et HCN2 canaux, le canal de HCN4 plus lent peut manifestent pas hyst&eacute;r&eacute;sis voltage-d&eacute;pendants. Nous avons &eacute;tudi&eacute; les propri&eacute;t&eacute;s &eacute;lectrophysiologiques des humains HCN4 canaux (hHCN4) et sa modulation par cAMP pour d&eacute;terminer si les hHCN4 pi&egrave;ces hyst&eacute;r&eacute;sis, &agrave; l&#39;aide de patch-clamp de la cellule unique dans les cellules HEK293 stablement transfected avec hHCN4. RT-PCR quantitative en temps r&eacute;el a &eacute;t&eacute; &eacute;galement utilis&eacute; pour d&eacute;terminer les niveaux d&#39;expression de HCNs dans le tissu cardiaque humaine. Voltage clamp analyse a r&eacute;v&eacute;l&eacute; que le courant hHCN4 (activation I(h)) dent&eacute;e dans le sens de d&eacute;polarisation plus tenue hyperpolaris&eacute; potentiels. Rampe triangulaire et protocoles de pince de potentiel d&#39;action a &eacute;galement r&eacute;v&egrave;lent hHCN4 hyst&eacute;r&eacute;sis. cAMP am&eacute;lior&eacute; i et d&eacute;cal&eacute; d&#39;activation dans la direction de d&eacute;polarisation, modifiant ainsi le comportement d&#39;hyst&eacute;r&eacute;sis intrins&egrave;que hHCN4. Analyse PCR quantitative du tissu humain noeud sino-auriculaire (SAN) a montr&eacute; que HCN4 repr&eacute;sente 75 % des HCNs dans SAN humaine tout en HCN1 (21 %), HCN2 (3 %) et HCN3 (0,7 %) constitue le reste. Nos r&eacute;sultats sugg&egrave;rent que la HCN4 est le sous-type HCN pr&eacute;dominant dans le SAN humain et qu&#39;i pr&eacute;sente un comportement d&eacute;pendant de la tension hyst&eacute;r&eacute;sis qui peut &ecirc;tre modifi&eacute; par le cAMP. Par cons&eacute;quent, hHCN4 hyst&eacute;r&eacute;sis potentiellement joue un r&ocirc;le crucial en humain SAN activit&eacute; pacemaker.

Hyst&eacute;r&eacute;sis dans les canaux de HCN4 humaine : une caract&eacute;ristique cruciale pouvant affecter le noeud sino-auriculaire pacemaker.

I hyperpolarization-attivato cyclic nucleotide-gated (HCN) canali modulano e regolano frequenza e ritmo cardiaco. &Egrave; stato suggerito che, a differenza dei canali HCN1 e HCN2, il canale HCN4 lento non possa esibire isteresi voltaggio-dipendenti. Abbiamo studiato le propriet&agrave; elettrofisiologiche di umano HCN4 (hHCN4) canali e sua modulazione da cAMP per determinare se hHCN4 esibisce isteresi, tramite cella singola patch-clamp in cellule HEK293 stabile transfected con hHCN4. RT-PCR quantitativa in tempo reale &egrave; stato utilizzato anche per determinare i livelli di espressione di HCNs nel tessuto cardiaco umano. Tensione-morsetto analisi hanno rivelato che corrente hHCN4 (attivazione I(h)) spostato in direzione depolarizing con maggiori potenzialit&agrave; di hyperpolarized holding. Rampa triangolare e potenziale d&#39;azione morsetto protocolli anche rivelarono hHCN4 isteresi. cAMP enhanced lettera e spostato attivazione in direzione depolarizing, modificando quindi il comportamento di isteresi hHCN4 intrinseca. Analisi PCR quantitativa del tessuto umano nodo senoatriale (SAN) ha mostrato che HCN4 rappresenta il 75% di HCNs in SAN umano mentre HCN1 (21%), HCN2 (3%) e HCN3 (0,7%) costituisce il resto. I nostri dati suggeriscono che HCN4 &egrave; il sottotipo predominante HCN in SAN umano e che lettera esibisce comportamento di isteresi di voltaggio-dipendenti che pu&ograve; essere modificato da cAMP. Pertanto, hHCN4 isteresi potenzialmente gioca un ruolo cruciale nel SAN umana attivit&agrave; pacemaking.

Isteresi nei canali HCN4 umani: una caratteristica cruciale che interessano potenzialmente pacemaking nodo senoatriale.

Los hiperpolarizaci&oacute;n c&iacute;clicos cerrada de nucle&oacute;tido (HCN) canales activados modulan y regulan la frecuencia y ritmo card&iacute;aco. Se ha sugerido que, a diferencia de los canales HCN1 y HCN2, el canal m&aacute;s lento de HCN4 no puede exhibir dependientes de voltaje hist&eacute;resis. Estudiamos las propiedades electrofisiol&oacute;gicas de HCN4 humana (hHCN4) canales y su modulaci&oacute;n por campo para determinar si hHCN4 exhibe hist&eacute;resis, mediante el uso de patch-clamp de unicelular en c&eacute;lulas HEK293 estable transfectadas con hHCN4. RT-PCR cuantitativa en tiempo real tambi&eacute;n se utiliz&oacute; para determinar los niveles de expresi&oacute;n de HCNs en tejido cardiaco humano. Abrazadera de tensi&oacute;n an&aacute;lisis revel&oacute; esa corriente hHCN4 (activaci&oacute;n de la I(h)) cambiado de puesto en la direcci&oacute;n de despolarizaci&oacute;n con m&aacute;s potencialidades de explotaci&oacute;n hyperpolarized. Rampa triangular y protocolos de abrazadera de potencial de acci&oacute;n tambi&eacute;n revelaron hHCN4 hist&eacute;resis. Campamento hab&iacute;a mejorado I(h) y cambi&oacute; la activaci&oacute;n en la direcci&oacute;n de despolarizaci&oacute;n, modificando el comportamiento de hist&eacute;resis hHCN4 intr&iacute;nseca. An&aacute;lisis por PCR cuantitativo de tejido humano n&oacute;dulo sinoauricular (SAN) demostr&oacute; que HCN4 representa el 75% de las HCNs en SAN humana mientras HCN1 (21%), HCN2 (3%) y HCN3 (0.7%) constituye el resto. Nuestros datos sugieren que el HCN4 es el subtipo predominante de HCN en el SAN humano y que I(h) exhibe un comportamiento hist&eacute;resis dependientes de voltaje que puede ser modificado por el campo. Por lo tanto, hHCN4 hist&eacute;resis potencialmente desempe&ntilde;a un papel crucial en SAN humana actividad pacemaking.

Hist&eacute;resis en canales de HCN4 humanos: una caracter&iacute;stica crucial podr&iacute;an afectar pacemaking del nodo sinusal.

This paper has shown that modern endodontics has progressed significantly in describing and treating pulpal and periradicular pathology. Current knowledge indicates that endodontic therapy should be evaluated as a complete unit and that each phase of treatment is completed to provide a foundation for rehabilitation. The phase format assessment of endodontic therapy success provides an outline for clinicians to objectively provide treatment in effort to conserve natural dentition.

Phase format treatment for endodontic therapy.

Heart rhythm disorders, or arrhythmias, are a leading cause of morbidity and mortality worldwide. Omega-3 polyunsaturated fatty acids (Ï‰3PUFAs), commonly found in fish oils and plant seeds, have recently emerged as potential anti-arrhythmic agents. The purpose of this review is to summarize the electrophysiological basis of the anti-arrhythmic properties of Ï‰3PUFAs from clinical, animal, and cellular research. Evidence of the anti-arrhythmic effects of Ï‰3PUFAs originated from epidemiological studies that correlated a low incidence of sudden cardiac death with high dietary Ï‰3PUFA intake. Subsequently, multiple clinical trials have confirmed the therapeutic effects of Ï‰3PUFAs in preventing sudden cardiac death and multiple other arrhythmia-related disorders. This has led basic scientists to investigate the effects of Ï‰3PUFAs on several ion channels including sodium, potassium, and calcium channels, as well as Na/Ca exchangers. Therefore, Ï‰3PUFAs may hold promise as safe and effective anti-arrhythmic agents. Nevertheless, further research is needed in areas such as: (1) identifying which form(s) of Ï‰3PUFAs (i.e., phospholipid, triglyceride, or free) is (are) responsible for anti-arrhythmic actions; and (2) developing reproducible methods for delivery so that the appropriate form and concentration may be present at the target site to prevent and treat arrhythmias.

Electrophysiological mechanisms of the anti-arrhythmic effects of omega-3 fatty acids.

Troubles du rythme cardiaque ou arythmies, sont des principales causes de morbidit&eacute; et de mortalit&eacute; dans le monde. Om&eacute;ga-3 acides gras polyinsatur&eacute;s (&omega;3PUFAs), que se trouves couramment dans les huiles de poisson et des graines de plantes, ont r&eacute;cemment &eacute;merg&eacute; comme agents anti-arythmiques potentiels. L&#39;objectif de cette r&eacute;vision est de r&eacute;sumer la base &eacute;lectrophysiologique des propri&eacute;t&eacute;s anti-arythmiques de &omega;3PUFAs de recherche clinique, animale et cellulaire. Preuve des effets anti-arythmiques de &omega;3PUFAs provient d&#39;&eacute;tudes &eacute;pid&eacute;miologiques qui correspondaient &agrave; une faible incidence de mort subite avec l&#39;apport de la haute &omega;3PUFA alimentaires. Par la suite, plusieurs essais cliniques ont confirm&eacute; les effets th&eacute;rapeutiques des &omega;3PUFAs dans la pr&eacute;vention de mort subite et plusieurs autres troubles arythmie. Cela a conduit les scientifiques &agrave; &eacute;tudier les effets de &omega;3PUFAs sur plusieurs canaux ioniques dont le sodium, potassium et les canaux calciques, ainsi que les &eacute;changeurs Na/Ca. Par cons&eacute;quent, &omega;3PUFAs peut tenir promesse aussi s&ucirc;res et efficaces des agents antiarythmiques. N&eacute;anmoins, recherches suppl&eacute;mentaires sont n&eacute;cessaires dans des domaines tels que: (1) identifier quels formulaires aupr&egrave;s de &omega;3PUFAs (c&#39;est-&agrave;-dire des phospholipides, des triglyc&eacute;rides, ou libre) est (sont) responsable des actions anti-arythmique ; et (2) d&eacute;veloppement de m&eacute;thodes reproductibles pour la livraison afin que la forme appropri&eacute;e et la concentration peuvent &ecirc;tre pr&eacute;sents sur le site de cible pour pr&eacute;venir et traiter les arythmies.

M&eacute;canismes &eacute;lectrophysiologiques des effets anti-arythmiques d&#39;acides gras om&eacute;ga-3.

Disturbi del ritmo cardiaco o aritmie, sono delle principali cause di morbilit&agrave; e mortalit&agrave; in tutto il mondo. Acidi grassi polinsaturi Omega-3 (&omega;3PUFAs), che comunemente si trovano negli oli di pesce e semi della pianta, hanno recentemente emerso come potenziali agenti antiaritmici. Lo scopo di questa recensione &egrave; di riassumere le basi elettrofisiologiche delle propriet&agrave; antiaritmici di &omega;3PUFAs dalla ricerca clinica, animale e cellulare. Prove degli effetti antiaritmici di &omega;3PUFAs ha avuto origine da studi epidemiologici che correlato a una bassa incidenza di morte cardiaca improvvisa con aspirazione ad alta &omega;3PUFA nella dieta. Successivamente, molteplici studi clinici hanno confermato gli effetti terapeutici del &omega;3PUFAs nella prevenzione della morte cardiaca improvvisa e molteplici altri disturbi di aritmia. Questo ha portato gli scienziati base per indagare gli effetti della &omega;3PUFAs su diversi canali ionici, tra cui sodio, potassio e canali di calcio, cos&igrave; come scambiatori di Na/Ca. Pertanto, &omega;3PUFAs pu&ograve; tenere la promessa agenti antiaritmici come sicuri ed efficaci. Tuttavia, ulteriore ricerca &egrave; necessaria in zone come: (1) identificare quali moduli di &omega;3PUFAs (cio&egrave;, fosfolipidi, trigliceridi, o libero) &egrave; (sono) responsabile delle azioni antiaritmici; e (2) metodi riproducibili in via di sviluppo per la consegna, affinch&eacute; la forma appropriata e la concentrazione possono essere presentino presso il sito di destinazione per prevenire e trattare le aritmie.

Meccanismi elettrofisiologici degli effetti antiaritmici degli acidi grassi omega-3.

Trastornos del ritmo cardiaco, o arritmias, son una causa importante de morbilidad y mortalidad en todo el mundo. &Aacute;cidos grasos poliinsaturados omega-3 (&omega;3PUFAs), com&uacute;nmente encontrados en los aceites de pescado y semillas de la planta, recientemente han surgido como potenciales agentes antiarr&iacute;tmicos. El prop&oacute;sito de esta revisi&oacute;n es resumir las bases electrofisiol&oacute;gicas de las propiedades antiarr&iacute;tmicas de &omega;3PUFAs de investigaci&oacute;n cl&iacute;nica, animal y celular. Evidencia de los efectos antiarr&iacute;tmicos de &omega;3PUFAs originadas de estudios epidemiol&oacute;gicos que correlacion&oacute; una baja incidencia de muerte s&uacute;bita con la toma de alta &omega;3PUFA diet&eacute;tica. Posteriormente, varios ensayos cl&iacute;nicos han confirmado los efectos terap&eacute;uticos de &omega;3PUFAs en la prevenci&oacute;n de muerte s&uacute;bita y varios otros trastornos relacionados con la arritmia. Esto ha llevado a los cient&iacute;ficos b&aacute;sicos para investigar los efectos de &omega;3PUFAs en varios canales de iones sodio, potasio y los canales de calcio, as&iacute; como intercambiadores Na/Ca. Por lo tanto, &omega;3PUFAs puede mantener promesa agentes antiarr&iacute;tmicos como seguros y efectivos. Sin embargo, se necesitan m&aacute;s investigaciones en &aacute;reas tales como: (1) identificar qu&eacute; formularios de &omega;3PUFAs (es decir, fosfol&iacute;pidos, triglic&eacute;ridos, o libre) es (son) responsable de acciones antiarr&iacute;tmicas; y (2) m&eacute;todos reproducibles en desarrollo para la entrega para que sean la forma apropiada y la concentraci&oacute;n presentan en el sitio de destino para prevenir y tratar las arritmias.

Mecanismos electrofisiol&oacute;gicos de los efectos antiarr&iacute;tmicos de &aacute;cidos grasos omega-3.

Anti-arrhythmic drugs have narrow therapeutic ranges and typically can engender harmful side effects. The intrapericardial (IP) delivery of anti-arrhythmic agents proposes to achieve higher myocardial levels while minimizing plasma concentrations, thus diminishing systemic side effects. Furthermore, IP delivery enables concentrations at the target site to be more precisely controlled. Our study objective was to compare the relative cardiac effects of intrapericardial administration of metoprolol to standard intravenous (IV) delivery in a swine surgical model. In order to answer the question of how IP metoprolol affects sinus tachycardia, atrial electrophysiology, and pharmacokinetics compared with IV delivery, a medial sternotomy was performed on 21 swine that were divided into three groups: (1) After inducing sinus tachycardia, metoprolol boluses were delivered IP (n = 4) or IV (n = 4); (2) metoprolol was administered either IP (n = 3) or IV (n = 3) with saline controls (n = 3), and electrophysiologic data were collected; (3) metoprolol levels were tracked both in the blood (IV, n = 2) and pericardial (IP, n = 2) fluid. After either IP or IV delivery of metoprolol, heart rates were lowered significantly to 70% and 73% of control rate, respectively. The therapeutic effect of IV-administered metoprolol was considerably reduced after 1 h but was sustained longer in the IP group. Additionally, ventricular contractility and mean arterial pressure parameters were significantly lower in IV-treated animals but were nearly unaffected in IP-treated animals. With IP administration, the elimination half-life of metoprolol in pericardial fluid was 14.4 min with negligible accumulations in the plasma, whereas with IV delivery, the elimination half-life in plasma was 11.1 min with negligible amounts found in the pericardial fluid. The targeted intrapericardial delivery of metoprolol effectively lowers heart rates for sustained periods of time, with minimal effect on either ventricular contractility or mean arterial pressure. We did not observe dramatic changes in induced atrial fibrillation times or refractory periods using this model.

Cardiac responses to the intrapericardial delivery of metoprolol: targeted delivery compared to intravenous administration.

M&eacute;dicaments anti-arythmiques ont des aires th&eacute;rapeutiques &eacute;troites et g&eacute;n&eacute;ralement peuvent engendrer des effets secondaires nocifs. La livraison intra-p&eacute;ricardique (IP) des agents anti-arythmiques se propose d&#39;atteindre des niveaux plus &eacute;lev&eacute;s de myocardiques tout en minimisant les concentrations plasmatiques, diminuant ainsi les effets secondaires syst&eacute;miques. De plus, livraison IP permet des concentrations sur le site de cible &agrave; contr&ocirc;ler plus pr&eacute;cis&eacute;ment. Notre objectif de l&#39;&eacute;tude &eacute;tait de comparer les effets cardiaques relatives d&#39;intra-p&eacute;ricardique administration de m&eacute;toprolol &agrave; la livraison par voie intraveineuse (IV) dans un mod&egrave;le chirurgical de porcs. Afin de r&eacute;pondre &agrave; la question de comment IP metoprolol affecte la tachycardie sinusale, &eacute;lectrophysiologie auriculaire et pharmacocin&eacute;tique par rapport &agrave; la prestation de IV, une sternotomie m&eacute;diane a &eacute;t&eacute; r&eacute;alis&eacute;e sur des 21 porcs qui ont &eacute;t&eacute; divis&eacute;s en trois groupes: (1) apr&egrave;s tachycardie sinusale induisant, bolus de m&eacute;toprolol ont &eacute;t&eacute; livr&eacute;es IP (n = 4) ou IV (n = 4) ; (2) metoprolol a &eacute;t&eacute; administr&eacute; IP (n = 3) ou IV (n = 3) avec contr&ocirc;les salines (n = 3) et &eacute;lectrophysiologiques sont collect&eacute;es ; (3) metoprolol niveaux ont &eacute;t&eacute; suivis dans le sang (IV, n = 2) et p&eacute;ricardique (IP, n = 2) liquide. Apr&egrave;s l&#39;accouchement soit IP ou IV de m&eacute;toprolol, fr&eacute;quences cardiaques ont &eacute;t&eacute; abaiss&eacute;s de mani&egrave;re significative &agrave; 70 % et 73 % de taux de contr&ocirc;le, respectivement. L&#39;effet th&eacute;rapeutique de m&eacute;toprolol IV-administr&eacute; a &eacute;t&eacute; consid&eacute;rablement r&eacute;duite apr&egrave;s 1 h, mais a &eacute;t&eacute; plus soutenue dans le groupe de la propri&eacute;t&eacute; intellectuelle. En outre, la contractilit&eacute; ventriculaire et la pression art&eacute;rielle moyenne param&egrave;tres &eacute;taient significativement plus faibles chez les animaux trait&eacute;s IV mais &eacute;taient presque pas affect&eacute;es chez les animaux trait&eacute;s IP. Avec l&#39;administration de la propri&eacute;t&eacute; intellectuelle, la demi-vie d&#39;&eacute;limination du m&eacute;toprolol au liquide p&eacute;ricardique &eacute;tait 14,4 min avec des accumulations de n&eacute;gligeables dans le plasma, alors qu&#39;avec livraison IV, la demi-vie d&#39;&eacute;limination plasmatique &eacute;tait 11,1 min avec des quantit&eacute;s n&eacute;gligeables dans le liquide p&eacute;ricardique. La livraison intra-p&eacute;ricardique cibl&eacute;e de m&eacute;toprolol diminue efficacement le rythme cardiaque pour des p&eacute;riodes prolong&eacute;es de temps, avec un effet minime sur la contractilit&eacute; ventriculaire ou la pression art&eacute;rielle moyenne. Nous n&#39;avons pas observ&eacute; bouleversements fois induit une fibrillation auriculaire ou p&eacute;riodes r&eacute;fractaires &agrave; l&#39;aide de ce mod&egrave;le.

Des r&eacute;ponses cardiaques &agrave; la livraison d&#39;intra-p&eacute;ricardique de m&eacute;toprolol : cibl&eacute;es par rapport &agrave; l&#39;administration intraveineuse de livraison.

Farmaci antiaritmici hanno stretti range terapeutici e in genere possono comportare effetti collaterali dannosi. La consegna di intrapericardial (IP) degli agenti antiaritmici si propone di raggiungere pi&ugrave; alti livelli del miocardio, riducendo al minimo le concentrazioni plasmatiche, diminuendo cos&igrave; gli effetti collaterali sistemici. Inoltre, consegna IP consente concentrazioni presso il sito di destinazione per essere pi&ugrave; precisamente controllato. Il nostro obiettivo di studio era di confrontare gli effetti cardiaci parente di intrapericardial somministrazione di Metoprololo per fornitura per via endovenosa (IV) in un modello chirurgico suina. Al fine di rispondere alla domanda di come IP metoprolol influisce Tachicardia sinusale, atriale elettrofisiologia e farmacocinetica rispetto con consegna IV, &egrave; stata eseguita una sternotomia mediana sulla 21 suina che sono stati divisi in tre gruppi: (1) dopo Tachicardia sinusale induzione, metoprololo boli furono consegnati IP (n = 4) o IV (n = 4); (2) Metoprololo &egrave; stato somministrato sia IP (n = 3) o IV (n = 3) con controlli salini (n = 3) ed elettrofisiologiche sono stati raccolti; (3) metoprololo livelli sono stati rilevati sia nel sangue (IV, n = 2) e pericardica (IP, n = 2) fluido. Dopo la consegna o IP o IV di Metoprololo, tassi di cuore sono stati abbassati significativamente al 70% e 73% del tasso di controllo, rispettivamente. L&#39;effetto terapeutico di Metoprololo somministrato IV &egrave; stata notevolmente ridotta dopo 1h ma &egrave; stata pi&ugrave; sostenuta nel gruppo di IP. Inoltre, contrattilit&agrave; ventricolare e parametri di pressione arteriosa media erano significativamente pi&ugrave; bassi negli animali trattati IV ma erano quasi inalterati negli animali trattati con IP. Con la somministrazione di IP, l&#39;emivita di eliminazione del metoprololo nel liquido pericardico era 14,4 min con accumuli trascurabili nel plasma, mentre con la consegna del IV, l&#39;emivita di eliminazione nel plasma era 11,1 min con importi trascurabili trovato nel liquido pericardico. La consegna di intrapericardial mirati di Metoprololo abbassa efficacemente frequenze cardiache per lunghi periodi di tempo, con un impatto minimo sulla contrattilit&agrave; ventricolare o pressione arteriosa media. Noi non ha rispettato i drammatici cambiamenti a volte indotta fibrillazione atriale o periodi refrattari utilizzando questo modello.

Cardiache risposte alla consegna intrapericardial di Metoprololo: mirati consegna rispetto alla somministrazione endovenosa.

Antiarr&iacute;tmicos tienen rangos terap&eacute;uticos estrechos y por lo general pueden generar efectos secundarios da&ntilde;inos. La entrega de intraperic&aacute;rdico (IP) de agentes antiarr&iacute;tmicos propone alcanzar niveles m&aacute;s altos del miocardio reduciendo al m&iacute;nimo las concentraciones plasm&aacute;ticas, disminuyendo as&iacute; los efectos secundarios sist&eacute;micos. Adem&aacute;s, entrega IP permite concentraciones en el sitio de destino para ser m&aacute;s exacto controlada. Nuestro objetivo de este estudio fue comparar los efectos card&iacute;acos relativos de intraperic&aacute;rdico administraci&oacute;n de metoprolol a entrega de (IV) intravenosa est&aacute;ndar en un modelo quir&uacute;rgico porcina. Con el fin de responder a la pregunta de c&oacute;mo afecta la IP metoprolol taquicardia atrial electrofisiolog&iacute;a y farmacocin&eacute;tica en comparaci&oacute;n con la entrega de la IV, una esternotom&iacute;a media fue realizado en 21 cerdos que fueron divididos en tres grupos: (1) despu&eacute;s que induce taquicardia, metoprolol bolos fueron entregados IP (n = 4) o IV (n = 4); (2) metoprolol se administr&oacute; ya sea IP (n = 3) o IV (n = 3) con controles de salinos (n = 3) y electrofisiol&oacute;gico se obtuvieron los datos; (3) metoprolol niveles fueron seguidos en la sangre (IV, n = 2) y peric&aacute;rdica (IP, n = 2) l&iacute;quido. Despu&eacute;s de la entrega IP o IV de metoprolol, frecuencias card&iacute;acas se redujeron significativamente al 70% y 73% de tasa de control, respectivamente. El efecto terap&eacute;utico de metoprolol IV administrado se redujo considerablemente despu&eacute;s de 1 h, pero se mantuvo m&aacute;s tiempo en el grupo IP. Adem&aacute;s, contractilidad ventricular y par&aacute;metros de la presi&oacute;n arterial media fueron significativamente inferiores en animales tratados con IV pero eran casi inafectados en animales tratados con IP. Con administraci&oacute;n de IP, la semivida de eliminaci&oacute;n del metoprolol en l&iacute;quido peric&aacute;rdico fue 14,4 min con acumulaciones insignificantes en el plasma, mientras que con la entrega de la IV, la vida media de eliminaci&oacute;n en plasma fue 11,1 min con cantidades insignificantes que se encuentran en el l&iacute;quido peric&aacute;rdico. La entrega de intraperic&aacute;rdico espec&iacute;ficas de metoprolol efectivamente baja frecuencias card&iacute;acas por per&iacute;odos prolongados de tiempo, con un efecto m&iacute;nimo sobre la contractilidad ventricular o la presi&oacute;n arterial media. No observamos cambios dram&aacute;ticos en fibrilaci&oacute;n auricular inducida por &eacute;pocas o per&iacute;odos refractarios utilizando este modelo.

Cardiacas responses to la entrega intraperic&aacute;rdico de metoprolol: objetivo parto comparada con la administraci&oacute;n intravenosa.

Understanding midbrain dopamine (DA) neuron differentiation is of importance, because of physiological and clinical implications of this neuronal subtype. We show that prolonged membrane depolarization induced by KCl treatment promotes DA neuron differentiation from neural precursor cells (NPCs) derived from embryonic ventral midbrain (VM). Interestingly, the depolarization-induced increase of DA neuron yields was not abolished by L-type calcium channel blockers, along with no depolarization-mediated change of intracellular calcium level in the VM-derived NPCs (VM-NPCs), suggesting that the depolarization effect is due to a calcium-independent mechanism. Experiments with labeled DA neuron progenitors indicate that membrane depolarization acts at the differentiation fate determination stage and promotes the expression of DA phenotype genes (tyrosine hydroxylase [TH] and DA transporter [DAT]). Recruitment of Nurr1, a transcription factor crucial for midbrain DA neuron development, to the promoter of TH gene was enhanced by depolarization, along with increases of histone 3 acetylation (H3Ac) and trimethylation of histone3 on lysine 4 (H3K4m3), and decreases of H3K9m3 and H3K27m3 in the consensus Nurr1 binding regions of TH promoter. Depolarization stimuli on differentiating VM-NPCs also induced dissociation of methyl CpG binding protein 2 and related repressor complex molecules (repressor element-1 silencing transcription factor corepressor and histone deacetylase 1) from the CpG sites of TH and DAT promoters. Based on these findings, we suggest that membrane depolarization promotes DA neuron differentiation by opening chromatin structures surrounding DA phenotype genes and inhibiting the binding of corepressors, thus allowing transcriptional activators such as Nurr1 to access DA neuron differentiation gene promoter regions.

Article	Year
Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin. Autonomic neuroscience : basic & clinical\| PubMed ID: 15507408	2004
The role of cavitation in acoustically activated drug delivery. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 16046023	2005
Reducing liposome size with ultrasound: bimodal size distributions. Journal of liposome research\| PubMed ID: 16556550	2006
The role of cavitation in liposome formation. Biophysical journal\| PubMed ID: 17766335	2007
Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias. American journal of physiology. Heart and circulatory physiology\| PubMed ID: 18326793	2008
Over-pressure suppresses ultrasonic-induced drug uptake. Ultrasound in medicine & biology\| PubMed ID: 19056161	2009
Not every bulb is a rose: a functional comparison of bulb suction devices. The Journal of surgical research\| PubMed ID: 19691976	2009
Stimulus overload 'video game epilepsy' causes seizures in young and old. JEMS : a journal of emergency medical services\| PubMed ID: 19897145	2009
Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking. Sheng li xue bao : [Acta physiologica Sinica]\| PubMed ID: 20179882	2010
Phase format treatment for endodontic therapy. Dentistry today\| PubMed ID: 20687435	2010
Electrophysiological mechanisms of the anti-arrhythmic effects of omega-3 fatty acids. Journal of cardiovascular translational research\| PubMed ID: 21125434	2011
Cardiac responses to the intrapericardial delivery of metoprolol: targeted delivery compared to intravenous administration. Journal of cardiovascular translational research\| PubMed ID: 21877256	2012
Prolonged membrane depolarization enhances midbrain dopamine neuron differentiation via epigenetic histone modifications. Stem cells (Dayton, Ohio)\| PubMed ID: 21922608	2011

Eric Richardson

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