We would like to give a big thanks to the Visible Heart Laboratory staff and students that have helped with this project: Nate Menninga, Lars Mattison and Megan Schmidt.

Bu protokol Minnesota Kurumsal Hayvan Bakımı ve Kullanımı Komitesi Üniversitesi tarafından onaylanmıştır. <img alt="Şekil 1" src="/files/ftp_upload/52600/52600fig1.jpg" /> Çalışma Paradigma 1. diyagramı Şekil <a href="https://www.jove.com/files/ftp_upload/52600/52600fig1large.jpg" target="_blank">bu rakamın daha büyük bir versiyonunu görmek için lütfen buraya tıklayınız.</a> Domuz 1. Cerrahi Hazırlık <ol><li> kas içi enjeksiyon yoluyla domuz (70-80 kg) için tiletamine / zilazipam Evi / kg 5-7mg yönetmek. bir kulak ven kateteri yerleştirin ve intravenöz erişim yoluyla 5-7 mg / kg Methohexital yönetmek. endotrakeal tüp ve ventilate ile hayvan entübe. </li><li> anestezi cerrahi düzlemi korumak için bir ev hava ve oksijen karışımı içinde izofluran&gt;% 1.2 MAC verin. Emin olun hayvan ANEST derin bir düzlemde olduğunulerine çene sesi olmaması için denetleme ve domuz için minimum alveolar konsantrasyonun üzerinde anestezi tutarak herhangi manipülasyonlar önce. İlk anestezik derinlik kontrolü çene sesi ve izofluran seviyelerinin yokluğu güvence tarafından yürütülen anestezi derin bir uçağı sağlamak için prosedür (&gt; 1.5 MAC) boyunca sürekli izlenmektedir. </li><li> Dikkatle koter ve künt diseksiyon ile sağ eksternal juguler ve karotis arter erişin. Dış juguler bir 8.5F Swan-Ganz kateteri yerleştirin ve 1.5 cc balonu şişirmek. Sonra ventrikül içine bir kama basıncı hissettim kadar pulmoner arter aşağı pulmoner kapaktan, sağ atrium ile çapraz. </li><li> balon Deflate ve bu pozisyonda kateter bırakın. balon kullanarak sağ atriyal basınç ve pulmoner arter basıncı kaydedin. Ayrıca, akciğer kama basıncı veya basınç kaydetmek (ya da akciğerler normal kabul edilir ise, o zaman da sol kaydetmekdeneme basıncı). NOT: Bu kateter da kardiyak output tahminleri sağlar. </li><li> Dış juguler ve sağ ventrikül sürekli rekor basınç içine ilave 5.0f balon basıncı kateter yerleştirin. </li><li> aort kapağı aracılığıyla 5.0f balon basıncı karotid arter kateter, prolapsusu yerleştirin ve sol ventrikül korumak. Bir basınç dönüştürücü bağlı 20 birim / ml heparinize salin ile tüm basınç kateterler yıkayın ve sol ventrikül tüm basınç verilerini kaydetmek, sağ ventrikül, pulmoner arter basıncı ve sağ atriyal basıncı (ve kardiyak output tahmin). </li><li> periferik izleme, gerçek-zamanlı kan basıncı ya da kan gazı izleme için 18F kateter yerleştirerek femoral arter dalı erişin. İşlem sırasında kayıt kalp hızı ve sıcaklığı. </li><li> Dikkatle koter ve künt diseksiyon ile sol dış juguler erişin. jugu iki 11.0F hemostaz introducers yerleştirinlar ve 0 ipek dikişlerle güvenli. introducers içinde yönetilebilir kateter yerleştirin. </li><li> floroskopi altında yer aktif sabitleme sağ atriyal apendiks ve sağ ventrikül apeks yol açar. NOT: Bir tespit kurşun implante kalp pili kalbi bağlayan bir ameliyatla takılan tel. </li><li> Bir programcı kullanan yakalamak için potansiyel ve test Connectanalyzer kabloları. 8V, 0.25 msn süresi parametreleri ayarlayın ve o zaman içsel hızından daha 10 bpm daha yüksek bir asgari kalp hızını ayarlayın. Her ilan için göreceli empedansını kaydedin. </li><li> sternocleidomastoid kasların ekleme yakınına kılıç şeklinde süreci medial cerrahi kesi yapmak. sternum kısmi medial diseksiyon etkinleştirmek için sternum (salma kemik) dan ön çıkıntı kaldırmak için bir sternum testeresi kullanın. sternal kemik yapısının geri kalan kısımları ile kesilmiş bir kesme kullanın. sternum-perikard ligament incelemek ve sternu gerim. </li><li> Plevra balataları gelen perikard ayırmak için künt diseksiyon kullanın. perikard medial sagital kesi (3-5 cm) yapın ve her köşesinde dört kare düğüm dikişlerle bir perikardiyal beşik oluşturmak (sağ, üst ve alt siteler, sol). </li><li> sol ventrikül apikal bölgede geçici bir bipolar kurşun yerleştirin ve sol atriyal apendiks içine tek kutuplu bir dalma geçici kalp pili kurşun yerleştirin. </li><li> Ötanazi uzaklaştırılmasıyla derin anestezi altında kalbi gerçekleştirilir. </li></ol> Elektrofizyolojik İzleme 2. Hazırlık <ol><li> Kardiyak Haritalama Sistemi. <ol><li> koparma kutusunda uygun ayarlara timsah klipler ile atriyal apendiks ventriküler epikardiyal bipolar pacing lead&#39;lerine ve epikardiyal yol açar bağlayın kalp haritalama sisteminde bir AF çalışması seçin. sisteme bir EKG ve topraklama pedleri bağlayın. </li></ol></li><li> Osiloskop ve Çim Stimülatör. <ol><li> bağlamakElektrik doğrulama için bir osiloskop bağlı bir Grass uyarıcısı için koparma kutusunda bipolar sol ventriküler pacing lead ve tek kutuplu atriyal kurşun. </li></ol></li><li> Elektrofizyolojik Uyarım Programlı. <ol><li> kalp pilinin üzerine bir kalp pili Place programcı telemetri kafasını sağ atriyal yol açar ve sağ ventrikül açar sabitleyin. kalp pili elektrodu stimülasyon (PES) çalışma seçmek ve 8V&#39;a parametrelerini ayarlamak; tüm hasta parametrelerini kaldırın. 400 ms (veya 300 ms) 8 bakliyat ayarlanmış kalp pili süresini ayarlayın. </li></ol></li></ol> Yerinde Çalışması 3. <ol><li> Refrakter Periyot: Çalışma Paradigma. <ol><li> Atriyal efektif refrakter periyodunu (AERP), atriyal ventriküler düğüm refrakter dönem (AVNERP) ve başlangıçtaki ventriküler efektif refrakter periyodunu (VERP) belirleyin ve bileşik / ilaç / kontrol tedavisinin 30 ve 60 dk sonrası perikardiyal teslim; Ek zaman noktalarında DES gibi ilave edilebilirIRED. </li></ol></li><li> Refrakter Periyot: Programcı Ayarları. <ol><li> 300 milisaniye pili en az izledi 8 adım (400 msn veya 300 msn) PES çalışma parametresini neden Burst. ventriküller / atrium kadar ilerleme hızını azaltın (sırasıyla) sözleşme başarısız. Bu pacing leadler&#39;inin algılama gelen not edilir; Böylece görece dirençli belirlenmesi. </li></ol></li></ol><img alt="şekil 2" src="/files/ftp_upload/52600/52600fig2.jpg" /> Şekil 2. EnSiteSystem: AERP, AVNERP ve VERP belirlenmesi <a href="https://www.jove.com/files/ftp_upload/52600/52600fig2large.jpg" target="_blank">, bu rakamın büyük halini görmek için lütfen buraya tıklayınız.</a> <ol start="3"><li> Parametreler: Göreli AF Yükü belirlenmesi. <ol><li> ., Yani AF sonlandırmak için 5 joule direkt kürekler ile atriyumları şok önce: 1 dakika sonra, en fazla 10 dakika AF içinde kalmasına izin, AF hayvanın kalbini Sustain. ElHer zaman noktasında 10 kata kadar ICIT AF indüksiyon. Bu çalışmada, dikkat edin. AF P dalgasının yokluğu ile düzensiz ritim olarak tanımlanmaktadır. </li></ol></li><li> AF Yükü: Çim Stimülatör ve Osiloskop Ayarları. <ol><li> dalma kalp pili kablosu ile sol atriyal apendiks (SAA) bir 2 sn darbe süresi ile 4 Hz teslim etmek Grass uyarıcısı için parametrelerini optimize; Standart bir osiloskop ile bu doğrulayın. AF ikna etmek için SAA tek bir darbe sunun. </li></ol></li></ol> 4. Kalp Eksplantasyonu ve Reanimasyon (Nakli Modeli) <ol><li> Aort Kök Kanül. <ol><li> Dikkatle çıkan aort etrafında perikard dokusu disseke ve kaldırmak 2.0 Ethibond dikiş pericardium.Suture iki nokta (dışında 2-3 cm) çıkan aort ve damar Heparin 30.000 birimleri yönetmek. </li><li> dikiş noktaları arasındaki aort kökü kanül yerleştirin ve aorta sabitleyin. basınçlı dağıtım sistemi sayesinde, t kaldırmakO konik Stylet ve kanül akışı için izin vermiyor bir kelepçe yerleştirin. </li></ol></li><li> Kardiyopleji hazırlanması. <ol><li> basınçlı torba aracılığıyla 150 mm / hg basınç altında çıkan aort içine soğuk Thomas kardiyoplejisi çözümü uygulayın. uzak ucunda bir 3-yollu vanasını ile basınçlandırılmıştır kardiyopleji bağlı bir sulama kateter elde edin. , Aort kökü kanül stop horoz sabitleyin kateter aracılığıyla kardiyoplejisinin sürekli bir floş bırakın ve aort kökü kanül sabitleyin. </li></ol></li><li> Çapraz Kelepçe. <ol><li> diyaframa sadece üstün bir atraumaticclamp 1-2 cm inferior vena kava kelepçe. Aort kökü kanül üstün çıkan aort üzerinde atravmatik açılı kamp 1-2 cm çıkan aort Kelepçe. </li></ol></li><li> Çapraz Kelepçe / Kardiyopleji. <ol><li> aort kapak ve perfus kapanış, aort kökü kanül kelepçe çıkarın ve 150 mm / aort kapak doğru hg de kardiyoplejisini floşkoroner arterler ing. </li><li> superior vena kava Kelepçe ve kalp basınç aşırı şekilde değil, pulmoner arter küçük bir kesi yapmak. Kalp, soğuk Krebs-Henseleit tampon maddesi banyosuna (asistolik), Vergi durdurulur ve göğüs ve yer kalp kaldırmak sonra (~ 3-8 ° C). </li></ol></li><li> Reanimasyon. <ol><li> büyük damarları cannulate ve Görünür Kalp yöntemleri kullanan kalbi hazırlamak (3). perfüze kalp 37 ± 5 ° C ulaştığında, epikardiyal yama elektrotlar aracılığıyla ventriküllere 34 J şok sunarak yerli sinüs ritminin. </li></ol></li></ol> Vitro Çalışma Paradigma 5. <ol><li> Sürekli 60 dakika sonrası reanimasyon için kalp fonksiyonunun izlenmesi. sadece mitral kapak altında bir LV görünümü: Sürekli bir kısa eksen ile 2D modunda ekokardiyografi izlemek. </li><li> ventrikül duvar kalınlığı ve ejeksiyon fraksiyonları her 10 dk sonrası yeniden canlandırma hesaplayın (aşağıya bakınız).Değerlendirme sürecinde -5 dakikada koroner sinüs (1 cc) ve her 5 dk numune almak. </li><li> İzleme. <ol><li> sol ve baskılara, akışlar ve hacim değişiklikleri de dahil olmak üzere sağ ventrikül, hem de hemodinami izleyin. </li></ol></li><li> Ekokardiyografi: Ejeksiyon Fraksiyonu. <ol><li> orta papiller kısa eksen görünümü yakalayan doğrudan kalbe bir transtorasik eko probu yerleştirin. denklem kullanılarak 4 odacıklı çalışma modunda her 10 dakikada ejeksiyon fraksiyonu (EF%) hesaplayın: LV Son Diastolik Hacim - LV sonu Sistolik Cilt X 100 / LV Son Diastolik hacmi </li></ol></li><li> Ekokardiyografi: Sol Ventriküler Duvar Kalınlığı. <ol><li> Bir saat sonra reanimasyon 10 dakika aralıklarla orta papiller kısa eksen penceresinden ventrikül duvar kalınlığı (cm) ölçün. Bir ekran kumpas kullanılarak sol karıncığın dört köşe ölçün ve ortalamasını alın. </li></ol></li><li> Miyokard Metabolizma. <ol><li> Bir steera yerleştirinKoroner sinüs (CS) de ble kateter. Örnek reanimasyon önce CS 5 dakika ve 1 saat boyunca her 5 dakika sonrası reanimasyon 1 cc. laktat ve glukoz düzeyleri için örneklerini test; diğer kan gazları da değerlendirilebilir. </li></ol></li></ol>

<ol>
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L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intrapericardial+beta-adrenergic+blockade+with+esmolol+exerts+a+potent+antitachycardic+effect+without+depressing+contractility.">Intrapericardial beta-adrenergic blockade with esmolol exerts a potent antitachycardic effect without depressing contractility.</a> J Cardiovasc Pharmacol. 36 (6), 722-727 (2000).</li><li>Jansen, B. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intrapericardial+delivery+enhances+cardiac+effects+of+sotalol+and+atenolol.">Intrapericardial delivery enhances cardiac effects of sotalol and atenolol.</a> J Cardiovasc Pharmacol. 44 (1), 50-56 (2004).</li><li>Vereckei, A., Gorski, J. C., Ujhelyi, M., Mehra, R., Zipes, D. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intrapericardial+ibutilide+administration+fails+to+terminate+pacing-induced+sustained+atrial+fibrillation+in+dogs.">Intrapericardial ibutilide administration fails to terminate pacing-induced sustained atrial fibrillation in dogs.</a> Cardiovas Drugs Ther. 18 (4), 269-277 (2004).</li><li>Kumar, K., Nguyen, K., Waxman, S., Nearing, B. D., Wellenius, G. A., Zhao, S. X., Verrier, R. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Potent+antifibrillatory+effects+of+intrapericardial+nitroglycerin+in+the+ischemic+porcine+heart.">Potent antifibrillatory effects of intrapericardial nitroglycerin in the ischemic porcine heart.</a> J Am Coll Cardiol. 41 (10), 1831-1837 (2003).</li><li>Fei, L., Baron, A. D., Henry, D. P., Zipes, D. 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The authors have nothing to disclose

Burada, perikard uzaya hedef teslim bileşiklerin potansiyel etkisini test etmek için benzersiz bir yaklaşım ortaya koymuştur. Bu çalışma, paradigma böylece çeşitli klinik ortamlarda doğrudan çeviri uygulamaları sağlayarak, eczacılık ürünleri veya deneysel bileşikler serbest mevcut piyasa test etmek için kullanılabilir. Bu tedavi stratejisi içinde perikard alana ilaç verilmesi için iki önemli klinik uygulamalar vardır: minimal 1) açık kalp veya invaziv cerrahi işlemler; ve 2) kalp nakli ve o...

Şu anda açık kalp işlemlerinde, klinisyenlerin sistemik antiaritmik ve diğer tedavi ajanları kullanmaktadır. Ancak, bu birçok hastada, zaten klinik tehlikeye özellikle isteyenler için sorunlu olabilir. Örneğin, damar tedavi kan basıncı veya böbrek fonksiyon bozukluğu sistemik damla neden olabilir; ayrıca, onlar anestezi yönetim sorunları ve / veya diğer uzun vadeli yan etkileri yaratabilir. Burada perikard uzaya farmakolojik ajanların uygulanması etkinliğini test etmek için bir model oluşturduk. Örneğin, bu yaklaşım, antiaritmik ilaçlar test kardiyak fonksiyonu ve / veya cerrahi prosedürler sonrasında miyokard teşvik geri kazanımını arttırabileceği bileşiklerin incelenmesi için de kullanılabilir. Intravenöz uygulama karşı perikard boşluğuna tedavilerin hedef teslim gözlenen faydaları olmuştur: Örneğin, bizim laboratuvar gösterdi antiaritmik ilaçların lokalize teslimkan basıncının 1 azalma minimize ederken metoprolol gibi ritmik ilaçlar, aritmi insidansı karşı koruyucudur. Bu hedef teslim stratejisi aynı zamanda sistemik seviyelerini en aza indirirken yüksek odak konsantrasyonları yönetmek için fırsat sağlar. Örneğin, yağ asitlerinin, venöz içine verilen düzeyi daha yüksek hemoliz neden olabilir, fakat perikardiyal Gönderme Bu endişe 2 en aza indirir. Bu çalışma paradigma perikard teslim bileşiklerin etkinliğini belirlemek için üç ana hedefleri oluşur: 1) refrakter tedavi öncesi atriyal ventriküler düğüm dönemleri, atriyum ve ventriküller, 30 ve 60 dakika tedavi sonrası yerinde belirlenmesinde; 2) göreli tedavi ve 30 ve 60 dk tedavi sonrası (ek zamannoktaları aşılamadan sonraki sık sık ilave edildi) o 3 inc canlandırdı edildikten sonra kalp 3) fonksiyonel analiz öncesi yerinde AF yükühemodinamik izleme, kalp hızı, koroner sinüsten örneklenmiş kalp metabolizmasını (laktat ve glukoz), ejeksiyon fraksiyonu (EF%) ve ventrikül duvar kalınlığı (cm) luding Bu tedavi stratejisi modeli etkilerini gözlemlemek için bize izin her 10 dk sonrası yeniden canlandırma izlenen sırasında ve açık kalp ameliyatı veya transplantasyon sonrası kardiyak aritmi ve / veya iskemik hasar insidansını azaltabilir farmakolojik ajanlar.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>SelectSecure&#174; 3830 lead</td>
			<td>Medtronic</td>
			<td>N/A</td>
			<td>Pacing Lead&#160;</td>
		</tr>
		<tr>
			<td>C304 Deflectable Catheter&#160;</td>
			<td>Medtronic</td>
			<td>N/A</td>
			<td>Steerable catheter for placing leads&#160;</td>
		</tr>
		<tr>
			<td>SelectSecure&#174; 3830 lead</td>
			<td>Medtronic</td>
			<td>N/A</td>
			<td>active fixation pacing leads&#160;</td>
		</tr>
		<tr>
			<td>Grass S48 Stimulator</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Electrical Stimulator&#160;</td>
		</tr>
		<tr>
			<td>Premium 6500 Unipolar Pacing&#160;</td>
			<td></td>
			<td>N/A</td>
			<td>Plunge pacing lead for LAA</td>
		</tr>
		<tr>
			<td>EnSite&#8482; Cardiac Mapping</td>
			<td></td>
			<td>N/A</td>
			<td>Electrophysiology mapping system</td>
		</tr>
		<tr>
			<td>CareLink Programer 2092</td>
			<td>Medtronic</td>
			<td>N/A</td>
			<td>programmer for pacing leads</td>
		</tr>
		<tr>
			<td>GEM II &#174; pacemaker&#160;</td>
			<td>Medtronic</td>
			<td>N/A</td>
			<td>pacemaker can&#160;</td>
		</tr>
		<tr>
			<td>DLP &#174; Aortic Root Cannula</td>
			<td>Medtronic</td>
			<td>N/A</td>
			<td>aortic root cannula for transplant&#160;</td>
		</tr>
		<tr>
			<td>C-Arm Fluoroscopy</td>
			<td>Ziehm&#160;</td>
			<td>N/A</td>
			<td>fluoroscopic imaging&#160;</td>
		</tr>
		<tr>
			<td>Oscilliscope</td>
			<td>Tektronix&#160;</td>
			<td>N/A</td>
			<td></td>
		</tr>
		<tr>
			<td>11F Hemostasis introducer</td>
			<td>SafeSheath</td>
			<td>N/A</td>
			<td>Hemostasis introducers</td>
		</tr>
		<tr>
			<td>Swan-Ganz Catheter 8.0F</td>
			<td>ICU Medical&#160;</td>
			<td>N/A</td>
			<td>thermal dilution catheter&#160;</td>
		</tr>
		<tr>
			<td>Venogram balloon&#160;</td>
			<td>Oscor</td>
			<td>N/A</td>
			<td>pressure monitoring&#160;</td>
		</tr>
		<tr>
			<td>Ultraview SL</td>
			<td>Spacelabs</td>
			<td>N/A</td>
			<td>EKG and blood pressure&#160;</td>
		</tr>
		<tr>
			<td>s/5 Avance</td>
			<td>General Electric</td>
			<td>N/A</td>
			<td>Anesthesia machine</td>
		</tr>
		<tr>
			<td>Atrial 6492 &#8211; Unipolar Temporary Atrial Pacing Lead</td>
			<td>Medtronic</td>
			<td>N/A</td>
			<td>temporary pacing lead&#160;</td>
		</tr>
		<tr>
			<td>VIVID i</td>
			<td>General Electric</td>
			<td></td>
			<td>2D electrocardiography unit&#160;</td>
		</tr>
	</tbody>
</table>

testing the efficacy of pharmacological agents in a pericardial target delivery model in the swine

Bugüne kadar birçok farmakolojik ajanlar tedavi etmek veya açık kalp durumlarda aritmi istenmeyen sistemik yan etkilere oluşturmak önlemek için kullanılır. Örneğin, damar içinden tatbik antiaritmik ilaçlar, zaten tehlikede olan kardiyak hastada sistemik basınç düşüşünü üretebilir. açık kalp prosedürlerini yerine getirirken, cerrahlar genellikle ya küçük bir bağlantı noktası oluşturmak veya kullanım için uygundur alanları oluşturmak için bir perikard beşik oluşturacaktır. istenmeyen yan etkiler olmadan miyokard dokusuna doğrudan hedef farmakolojik doğum (antiaritmik veya iskemik önkoşullama ajanlar) Bu erişim verimleri imkanları. Biz perikard sıvısı içinde hedef teslimat için farmakolojik ajanların test edilmesine yönelik bir domuz modeli geliştirdik. Tam anestezi iken, her bir hayvan sol ve sağ ventrikül basınç kateter yanı sıra Swan-Ganz kateteri ile cihazlarıya ve kalp pili kabloları sağ atriyal apendiks ve sağ yerleştirildiventrikül. Medial sternotomi sonra gerçekleştirildi ve bir perikard erişim beşiği yaratıldı; Dalma ilerleme hızı talebi sol atriyal apendiks yerleştirildi ve iki kutuplu bir ilerleme hızı talebi sol ventrikül içine yerleştirilmiştir. Bir programcı ve bir kalp haritalama sistemi, atrioventriküler düğüm (AVN) refrakter periyodunu kullanarak, atriumlar ve karıncıklar tespit edildi. Buna ek olarak, atriyal fibrilasyon (AF) indüksiyon gözlenmiştir AF bir Grass uyarıcı ve saati kullanılarak üretildi. Bu ölçümler tedaviden önce, hem de 30 dakika karıştırıldı ve perikardiyal tedaviden sonra 60 dakika için gerçekleştirilmiştir. Ek süre noktaları seçilen çalışmalar için eklenmiştir. Bundan sonra, kalp cardiopleged ve dört odacık çalışma modunda reanimated edildi. Basınç ölçümleri ve fonksiyon reanimasyon sonra 1 saat süre ile kaydedildi. Bu tedavi stratejisi modeli sırasında ve af kardiyak aritmi ve / veya iskemik hasar insidansını azaltabilir farmakolojik ajanların etkilerini gözlemlemek için bize izinter açık kalp ameliyatı.

Bu sonuçlar domuzlarda farmakolojik ajanların bu hedef dağıtım modeli kullanılarak toplanabilir veri karakteristiktir. Bu veriler yerinde bir DHA infüzyonu takiben bu ventrikül efektif refrakter dönemler (VERP) dikkate değer artışlar gösterdi. Buna ek olarak, veri in vitro kontrol ile karşılaştırıldığında DHA, ventriküler basınç artışı oluşturur. DHA tedavi gönlünde LV basınç çeşitli zaman noktalarında kontrole kıyasla anlamlı olarak yüksek bulundu. Bu veriler, <em...

Watch this Scientific Journal Video about Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine at JoVE.com

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

We have developed a swine model for the target delivery of pharmacological agents within the pericardial space/fluid. Using this approach, the relative benefits of administered agents on induced atrial fibrillation, relative refractory periods and/or ischemic protection can be investigated.

Domuzda bir perikard Hedef Teslim Modelinde Farmakolojik Ajanlar Etkilerinin Test

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

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

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8.2K Görüntüleme.  University of Minnesota. We have developed a swine model for the target delivery of pharmacological agents within the pericardial space/fluid. Using this approach, the relative benefits of administered agents on induced atrial fibrillation, relative refractory periods and/or ischemic protection can be investigated. 

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

Making Sense of Listening: The IMAP Test Battery

The ability to hear is only the first step towards making sense of the range of information contained in an auditory signal. Of equal importance are the abilities to extract and use the information encoded in the auditory signal. We refer to these as listening skills (or auditory processing AP). Deficits in these skills are associated with delayed language and literacy development, though the nature of the relevant deficits and their causal connection with these delays is hotly debated.
When a child is referred to a health professional with normal hearing and unexplained difficulties in listening, or associated delays in language or literacy development, they should ideally be assessed with a combination of psychoacoustic (AP) tests, suitable for children and for use in a clinic, together with cognitive tests to measure attention, working memory, IQ, and language skills. Such a detailed examination needs to be relatively short and within the technical capability of any suitably qualified professional. Current tests for the presence of AP deficits tend to be poorly constructed and inadequately validated within the normal population. They have little or no reference to the presenting symptoms of the child, and typically include a linguistic component. Poor performance may thus reflect problems with language rather than with AP. To assist in the assessment of children with listening difficulties, pediatric audiologists need a single, standardized child-appropriate test battery based on the use of language-free stimuli.
We present the IMAP test battery which was developed at the MRC Institute of Hearing Research to supplement tests currently used to investigate cases of suspected AP deficits. IMAP assesses a range of relevant auditory and cognitive skills and takes about one hour to complete. It has been standardized in 1500 normally-hearing children from across the UK, aged 6-11 years. Since its development, it has been successfully used in a number of large scale studies both in the UK and the USA. IMAP provides measures for separating out sensory from cognitive contributions to hearing. It further limits confounds due to procedural effects by presenting tests in a child-friendly game-format. Stimulus-generation, management of test protocols and control of test presentation is mediated by the IHR-STAR software platform. This provides a standardized methodology for a range of applications and ensures replicable procedures across testers. IHR-STAR provides a flexible, user-programmable environment that currently has additional applications for hearing screening, mapping cochlear implant electrodes, and academic research or teaching.

A test battery (IMAP) for performing an in-depth assessment of auditory and cognitive abilities contributing to listening skills is described. It is quick to administer, child-friendly and free from linguistic confounds. Stimulus generation and protocol management are controlled via a software platform (IHR-STAR) to ensure replicable procedures.

Dinlemede Making Sense IMAP Test Batarya:

The ability to hear is only the first step towards making sense of the range of information contained in an auditory signal. Of equal importance are the ...

Tıp

A Swine Model of Neonatal Asphyxia

Annually more than 1 million neonates die worldwide as related to asphyxia. Asphyxiated neonates commonly have multi-organ failure including hypotension, perfusion deficit, hypoxic-ischemic encephalopathy, pulmonary hypertension, vasculopathic enterocolitis, renal failure and thrombo-embolic complications. Animal models are developed to help us understand the patho-physiology and pharmacology of neonatal asphyxia. In comparison to rodents and newborn lambs, the newborn piglet has been proven to be a valuable model. The newborn piglet has several advantages including similar development as that of 36-38 weeks human fetus with comparable body systems, large body size (&tilde;1.5-2 kg at birth) that allows the instrumentation and monitoring of the animal and controls the confounding variables of hypoxia and hemodynamic derangements.
We here describe an experimental protocol to simulate neonatal asphyxia and allow us to examine the systemic and regional hemodynamic changes during the asphyxiating and reoxygenation process as well as the respective effects of interventions. Further, the model has the advantage of studying multi-organ failure or dysfunction simultaneously and the interaction with various body systems. The experimental model is a non-survival procedure that involves the surgical instrumentation of newborn piglets (1-3 day-old and 1.5-2.5 kg weight, mixed breed) to allow the establishment of mechanical ventilation, vascular (arterial and central venous) access and the placement of catheters and flow probes (Transonic Inc.) for the continuously monitoring of intra-vascular pressure and blood flow across different arteries including main pulmonary, common carotid, superior mesenteric and left renal arteries. Using these surgically instrumented piglets, after stabilization for 30-60 minutes as defined by Z&lt;10% variation in hemodynamic parameters and normal blood gases, we commence an experimental protocol of severe hypoxemia which is induced via normocapnic alveolar hypoxia. The piglet is ventilated with 10-15% oxygen by increasing the inhaled concentration of nitrogen gas for 2h, aiming for arterial oxygen saturations of 30-40%. This degree of hypoxemia will produce clinical asphyxia with severe metabolic acidosis, systemic hypotension and cardiogenic shock with hypoperfusion to vital organs. The hypoxia is followed by reoxygenation with 100% oxygen for 0.5h and then 21% oxygen for 3.5h. Pharmacologic interventions can be introduced in due course and their effects investigated in a blinded, block-randomized fashion.

Large animal models have good translational values in the examination of physiology and pharmacology of neonatal asphyxia. Using newborn piglets, we develop an experimental protocol to simulate neonatal asphyxia which has advantages of studying the systemic and regional hemodynamics, oxygen transport with biochemical and pathologic pathways and correlations.

Yenidoğan Asfiksi Bir Domuz Modeli

Annually more than 1 million neonates die worldwide as related to asphyxia. Asphyxiated neonates commonly have multi-organ failure including hypotension, ...

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials.

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis ALS

A mouse model for amyotrophic lateral sclerosis (ALS) is examined clinically and behaviorally. As a prerequisite for an accompanying immunohistological analysis the preparation of the spinal cord is depicted in detail.

Amyotrofik Lateral Skleroz için Fare Modeli (ALS) Klinik Test ve Omurilik Kaldırma

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 ...

Excitotoxic Stimulation of Brain Microslices as an In vitro Model of Stroke

Examining molecular mechanisms involved in neuropathological conditions, such as ischemic stroke, can be difficult when using whole animal systems. As such, primary or &#39;neuronal-like&#39; cell culture systems are commonly utilized. While&#160;these systems are relatively easy to work with, and are useful model systems in which various functional outcomes (such as cell death) can be readily quantified, the examined outcomes and pathways in cultured immature neurons (such as excitotoxicity-mediated cell death pathways) are not necessarily the same as those observed in mature brain, or in intact tissue. Therefore, there is the need to develop models in which cellular mechanisms in mature neural tissue can be examined. We have developed an in vitro technique that can be used to investigate a variety of molecular pathways in intact nervous tissue. The technique described herein utilizes rat cortical tissue, but this technique can be adapted to use tissue from a variety of species (such as mouse, rabbit, guinea pig, and chicken) or brain regions (for example, hippocampus, striatum, etc.). Additionally, a variety of stimulations/treatments can be used (for example, excitotoxic, administration of inhibitors, etc.). In conclusion, the brain slice model described herein can be used to examine a variety of molecular mechanisms involved in excitotoxicity-mediated brain injury.

Excitotoxic Stimulation of Brain Microslices as an In vitro Model of Stroke

We have developed a brain slice model which can be used to examine molecular mechanisms involved in excitotoxicity-mediated brain injury.&#160;This technique generates viable mature brain tissue and reduces animal numbers required for experimentation, whilst keeping the neuronal circuitry, cellular interactions, and postsynaptic compartments partly intact.

Bir olarak Beyin Microslices arasında excitotoxic uyarılması<em&gt; In vitro</em&gt; İnme Model

Examining molecular mechanisms involved in neuropathological conditions, such as ischemic stroke, can be difficult when using whole animal systems. As ...

Surgical Placement of Catheters for Long-term Cardiovascular Exercise Testing in Swine

This protocol describes the surgical procedure to chronically instrument swine and the procedure to exercise swine on a motor-driven treadmill. Early cardiopulmonary dysfunction is difficult to diagnose, particularly in animal models, as cardiopulmonary function is often measured invasively, requiring anesthesia. As many anesthetic agents are cardiodepressive, subtle changes in cardiovascular function may be masked. In contrast, chronic instrumentation allows for measurement of cardiopulmonary function in the awake state, so that measurements can be obtained under quiet resting conditions, without the effects of anesthesia and acute surgical trauma. Furthermore, when animals are properly trained, measurements can also be obtained during graded treadmill exercise.
Flow probes are placed around the aorta or pulmonary artery for measurement of cardiac output and around the left anterior descending coronary artery for measurement of coronary blood flow. Fluid-filled catheters are implanted in the aorta, pulmonary artery, left atrium, left ventricle and right ventricle for pressure measurement and blood sampling. In addition, a 20 G&#160;catheter is positioned in the anterior interventricular vein to allow coronary venous blood sampling.
After a week of recovery, swine are placed on a motor-driven treadmill, the catheters are connected to pressure and flow meters, and swine are subjected to a five-stage progressive exercise protocol, with each stage lasting 3 min. Hemodynamic signals are continuously recorded and blood samples are taken during the last 30 sec of each exercise stage.
The major advantage of studying chronically instrumented animals is that it allows serial assessment of cardiopulmonary function, not only at rest but also during physical stress such as exercise. Moreover, cardiopulmonary function can be assessed repeatedly during disease development and during chronic treatment, thereby increasing statistical power and hence limiting the number of animals required for a study.

Here we present a protocol to assess cardiopulmonary function in awake swine, at rest and during graded treadmill exercise. Chronic instrumentation allows for repeated hemodynamic measurements uninfluenced by cardiodepressive anesthetic agents.

Domuz uzun süreli Kardiyovasküler Egzersiz Testi için Kateter Cerrahi Yerleştirme

This protocol describes the surgical procedure to chronically instrument swine and the procedure to exercise swine on a motor-driven treadmill. Early ...

Hemocompatibility Testing of Blood-Contacting Implants in a Flow Loop Model Mimicking Human Blood Flow

The growing use of medical devices (e.g., vascular grafts, stents, and cardiac catheters) for temporary or permanent purposes that remain in the body&#39;s circulatory system demands a reliable and multiparametric approach that evaluates the possible hematologic complications caused by these devices (i.e., activation and destruction of blood components). Comprehensive in vitro hemocompatibility testing of blood-contacting implants is the first step towards successful in vivo implementation. Therefore, extensive analysis according to the International Organization for Standardization 10993-4 (ISO 10993-4) is mandatory prior to clinical application. The presented flow loop describes a sensitive model to analyze the hemostatic performance of stents (in this case, neurovascular) and reveal adverse effects. The use of fresh human whole blood and gentle blood sampling are essential to avoid the preactivation of blood. The blood is perfused through a heparinized tubing containing the test specimen by using a peristaltic pump at a rate of 150 mL/min at 37 &#176;C for 60 min. Before and after perfusion, hematologic markers (i.e., blood cell count, hemoglobin, hematocrit, and plasmatic markers) indicating the activation of leukocytes (polymorphonuclear [PMN]-elastase), platelets (&#946;-thromboglobulin [&#946;-TG]), the coagulation system (thombin-antithrombin III [TAT]), and the complement cascade (SC5b-9) are analyzed. In conclusion, we present an essential and reliable model for extensive hemocompatibility testing of stents and other blood-contacting devices prior to clinical application.

This protocol describes a comprehensive hemocompatibility evaluation of blood-contacting devices using laser-cut neurovascular implants. A flow loop model with fresh, heparinized human blood is applied to mimic blood flow. After perfusion, various hematologic markers are analyzed and compared to the values gained directly after blood collection for hemocompatibility evaluation of the tested devices.

İnsan Kan Akışını Taklit Eden Akış Döngüsü Modelinde Kanla Temas Eden İmplantların Hemokomuuyum Testi

The growing use of medical devices (e.g., vascular grafts, stents, and cardiac catheters) for temporary or permanent purposes that remain in the ...

Standardized Model of Ventricular Fibrillation and Advanced Cardiac Life Support in Swine

Cardiopulmonary resuscitation after cardiac arrest, independent of its origin, is a regularly encountered medical emergency in hospitals as well as preclinical settings. Prospective randomized trials in human subjects are difficult to design and ethically ambiguous, which results in a lack of evidence-based therapies. The model presented in this report represents one of the most common causes of cardiac arrests, ventricular fibrillation, in a standardized setting in a large animal model. This allows for reproducible observations and various therapeutic interventions under clinically accurate conditions, hence facilitating the generation of better evidence and eventually the potential for improved medical treatment.

Cardiopulmonary resuscitation and defibrillation are the only effective therapeutic options during cardiac arrest caused by ventricular fibrillation. This model presents a standardized regimen to induce, assess, and treat this physiological state in a porcine model, thus providing a clinical approach with various opportunities for data collection and analysis.

Domuzda Standart Ventriküler Fibrilasyon Ve İleri Kardiyak Yaşam Desteği Modeli

Cardiopulmonary resuscitation after cardiac arrest, independent of its origin, is a regularly encountered medical emergency in hospitals as well as ...

Intratracheal Administration of Dry Powder Formulation in Mice

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

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

Farelerde Kuru Toz Formülasyonunun Intratrakial Yönetimi

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

Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a considerable proportion of coronary artery disease patients remain symptomatic. Gene therapy-mediated therapeutic angiogenesis offers a novel therapeutic method for improving myocardial perfusion and relieving symptoms. Gene therapy with different angiogenic factors has been studied in few clinical trials. Due to the novelty of the method, the progress of myocardial gene therapy is a continuous path from bench to bedside. Therefore, large animal models are needed for evaluating the safety and efficacy. The more the large animal model identifies the original disease and the endpoints used in clinics, the more predictable outcomes are from clinical trials. Here, we introduce a large animal model for evaluating the efficacy of the gene therapy in the ischemic porcine heart. We use clinically relevant imaging methods such as ultrasound imaging and 15H2O-PET. For targeting the gene transfers into the desired area, electroanatomical mapping is used. The aim of this method is: (1) to mimic chronic coronary artery disease, (2) to induce therapeutic angiogenesis at hypoxic areas of the heart, and (3) to evaluate the safety and efficacy of the gene therapy by using relevant endpoints.

Myocardial gene therapy for ischemic heart disease holds great promise for future therapeutics. Here, we introduce a large animal model for evaluating the efficacy of gene therapy in the ischemic heart.

İskemik Kalpte Gen Tedavisinin Etkinliğini Değerlendirmek İçin Büyük Hayvan Modeli

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a ...

Endotracheal Intubation Using a Flexible Intubation Endoscope as a Standardized Model for Safe Airway Management in Swine

Endotracheal intubation is often a basic requirement for translational research in porcine models for various interventions that require a secured airway or high ventilation pressures. Endotracheal intubation is a challenging skill,&#160;requiring a minimum number of successful endotracheal intubations to achieve a high success rate under optimal conditions, which is often unachievable for non-anaesthesiology researchers. Due to the specific porcine airway anatomy, a difficult airway can usually be assumed. The impossibility of establishing a secure airway can result in injury, adverse events, or death of the laboratory animal. Using a prospective, randomized, controlled evaluation approach, it has been shown that fiberoptic-assisted endotracheal intubation takes longer but has a higher first-pass success rate than conventional intubation without causing clinically relevant drops in oxygen saturation. This model presents a standardized regimen for endoscopically guided endotracheal intubation, providing a secured airway, especially for researchers who are inexperienced in the technique of endotracheal intubation via direct laryngoscopy. This procedure is expected to minimize animal suffering and unnecessary animal losses.

The use of pigs in research has increased in recent years. Nevertheless, pigs are characterized by difficult airway anatomy. By demonstrating how to perform endoscopically guided endotracheal intubation, the present protocol aims to further increase laboratory animals' safety to avoid animal suffering and unnecessary death.

Domuzlarda Güvenli Hava Yolu Yönetimi için Standartlaştırılmış Bir Model Olarak Esnek Entübasyon Endoskobu Kullanılarak Endotrakeal Entübasyon

Endotracheal intubation is often a basic requirement for translational research in porcine models for various interventions that require a secured airway ...