scholarly journals An in vivo pig model for testing novel PET radioligands targeting cerebral protein aggregates

2022 ◽  
Author(s):  
Nakul Ravi Raval ◽  
Arafat Nasser ◽  
Clara Aabye Madsen ◽  
Natalie Beschorner ◽  
Emily Eufaula Beaman ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Occipital Cortex ◽  
Pig Model ◽  
Large Animal Model ◽  
Neurosurgical Procedures ◽  
Large Animal ◽  
Human Brain Tissue ◽  
Clinical Tool ◽  
Reference Tissue ◽  
Postmortem Human Brain

Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-β or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated α-synuclein, which is seen in, e.g., Parkinson's Disease. Access to a large animal model with α-synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here established a pig model with cerebral injections of α-synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimer's disease (AD) or dementia with Lewy body (DLB) into the pig's brain using minimally invasive surgery and validated against saline injections. In the absence of a suitable α-synuclein radioligand, we validated the model with an unselective amyloid-β tracer [11C]PIB, which has a high affinity for β-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier function was intact. A few hours post-injection, pigs were PET scanned with [11C]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [11C]PIB uptake in AD-homogenate-injected regions and two times higher uptake in α-synuclein-preformed-fibrils-injected regions compared to the saline-injected regions. The [11C]PIB uptake was the same in the occipital cortex, cerebellum, DLB-homogenate, and saline-injected regions. With its large brains and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.

End-to-side nerve repair in a large animal model: how does it compare with conventional methods of nerve repair?

2012 ◽  
Vol 38 (2) ◽  
pp. 192-202 ◽  
Author(s):  
S. J. A. Kettle ◽  
N. E. Starritt ◽  
M. A. Glasby ◽  
T. E. J. Hems
Keyword(s):  
Nerve Regeneration ◽  
Functional Outcomes ◽  
Axon Regeneration ◽  
Nerve Repair ◽  
Large Animal Model ◽  
Control Group ◽  
Large Animal ◽  
Salvage Procedure ◽  
Clinical Tool ◽  
Sheep Model

A large animal (sheep) model was used to compare nerve axon regeneration and return of muscle function after a median-to-ulnar nerve end-to-side neurorrhaphy technique with conventional, clinically established, methods of nerve repair and untreated controls. Three groups of sheep were allocated to end-to-side repair (12 animals), a conventional method of nerve repair (18 animals), or a control group (eight animals). After a year nerve repairs were assessed electrophysiologically and histologically, and the muscles supplied by the repaired nerves were assessed physiologically. There were no significant differences in the outcomes of nerve repair between different conventional techniques. Half of the end-to-side nerve repairs supported nerve regeneration. The functional outcomes of the end-to-side repairs were inferior to conventional techniques which were, in turn, inferior to controls. End-to-side neurorrhaphy supported nerve regeneration, but the reliability of this technique is called into question and its use as a clinical tool can only be recommended as a salvage procedure.

DEVELOPMENT OF A LARGE ANIMAL MODEL OF OPIATE ADDICTION TO EVALUATE CARDIOVASCULAR FUNCTION.

Analgesia ◽  
1995 ◽  
Vol 1 (4) ◽  
pp. 598-602 ◽  
Author(s):  
L.D. Napier ◽  
Z. Mateo ◽  
D.A. Yoshishige ◽  
B.A. Barron ◽  
J.L. Caffrey
Keyword(s):  
Animal Model ◽  
Cardiovascular Function ◽  
Large Animal Model ◽  
Opiate Addiction ◽  
Large Animal

scholarly journals A novel large animal model of smoke inhalation-induced acute respiratory distress syndrome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Premila D. Leiphrakpam ◽  
Hannah R. Weber ◽  
Andrea McCain ◽  
Roser Romaguera Matas ◽  
Ernesto Martinez Duarte ◽  
...  
Keyword(s):  
Animal Model ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Distress Syndrome ◽  
Inhalation Injury ◽  
Smoke Inhalation ◽  
Large Animal Model ◽  
Large Animal ◽  
X Ray ◽  
Chest X Ray

Abstract Background Acute respiratory distress syndrome (ARDS) is multifactorial and can result from sepsis, trauma, or pneumonia, amongst other primary pathologies. It is one of the major causes of death in critically ill patients with a reported mortality rate up to 45%. The present study focuses on the development of a large animal model of smoke inhalation-induced ARDS in an effort to provide the scientific community with a reliable, reproducible large animal model of isolated toxic inhalation injury-induced ARDS. Methods Animals (n = 21) were exposed to smoke under general anesthesia for 1 to 2 h (median smoke exposure = 0.5 to 1 L of oak wood smoke) after the ultrasound-guided placement of carotid, pulmonary, and femoral artery catheters. Peripheral oxygen saturation (SpO2), vital signs, and ventilator parameters were monitored throughout the procedure. Chest x-ray, carotid, femoral and pulmonary artery blood samples were collected before, during, and after smoke exposure. Animals were euthanized and lung tissue collected for analysis 48 h after smoke inhalation. Results Animals developed ARDS 48 h after smoke inhalation as reflected by a decrease in SpO2 by approximately 31%, PaO2/FiO2 ratio by approximately 208 (50%), and development of bilateral, diffuse infiltrates on chest x-ray. Study animals also demonstrated a significant increase in IL-6 level, lung tissue injury score and wet/dry ratio, as well as changes in other arterial blood gas (ABG) parameters. Conclusions This study reports, for the first time, a novel large animal model of isolated smoke inhalation-induced ARDS without confounding variables such as cutaneous burn injury. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury or for development of novel therapeutics.

scholarly journals Central Noradrenergic Neurotransmission and Weight Loss 6 Months After Gastric Bypass Surgery in Patients with Severe Obesity

2021 ◽  
Author(s):  
J. Marvin Soeder ◽  
Julia Luthardt ◽  
Michael Rullmann ◽  
Georg A. Becker ◽  
Mohammed K. Hankir ◽  
...  
Keyword(s):  
Weight Loss ◽  
Gastric Bypass ◽  
Severe Obesity ◽  
Occipital Cortex ◽  
Brain Regions ◽  
General Tendency ◽  
Strong Positive Correlation ◽  
Reference Tissue ◽  
Efficient Treatment ◽  
Post Surgery

Abstract Purpose Roux-en-Y gastric bypass (RYGB) surgery is currently the most efficient treatment to achieve long-term weight loss in individuals with severe obesity. This is largely attributed to marked reductions in food intake mediated in part by changes in gut-brain communication. Here, we investigated for the first time whether weight loss after RYGB is associated with alterations in central noradrenaline (NA) neurotransmission. Materials and Methods We longitudinally studied 10 individuals with severe obesity (8 females; age 43.9 ± 13.1 years; body mass index (BMI) 46.5 ± 4.8 kg/m2) using (S,S)-[11C]O-methylreboxetine and positron emission tomography to estimate NA transporter (NAT) availability before and 6 months after surgery. NAT distribution volume ratios (DVR) were calculated by volume-of-interest analysis and the two-parameter multilinear reference tissue model (reference region: occipital cortex). Results The participants responded to RYGB surgery with a reduction in BMI of 12.0 ± 3.5 kg/m2 (p < 0.001) from baseline. This was paralleled by a significant reduction in DVR in the dorsolateral prefrontal cortex (pre-surgery 1.12 ± 0.04 vs. post-surgery 1.07 ± 0.04; p = 0.019) and a general tendency towards reduced DVR throughout the brain. Furthermore, we found a strong positive correlation between pre-surgery DVR in hypothalamus and the change in BMI (r = 0.78; p = 0.01). Conclusion Reductions in BMI after RYGB surgery are associated with NAT availability in brain regions responsible for decision-making and homeostasis. However, these results need further validation in larger cohorts, to assess whether brain NAT availability could prognosticate the outcome of RYGB on BMI. Graphical abstract

scholarly journals Development of a porcine model of emergency resternotomy at a low-volume cardiac surgery centre

2020 ◽  
Vol 31 (6) ◽  
pp. 803-805
Author(s):  
Timothy M Guenther ◽  
Sarah A Chen ◽  
Joshua D Gustafson ◽  
Curtis J Wozniak ◽  
Bob Kiaii
Keyword(s):  
Intensive Care Unit ◽  
Cardiac Surgery ◽  
Porcine Model ◽  
Comfort Level ◽  
Large Animal Model ◽  
Large Animal ◽  
Training Environment ◽  
Life Saving ◽  
Simulation Scenario ◽  
Low Volume

Abstract Emergency resternotomy in the intensive care unit (ICU) is a rarely performed, yet potentially life-saving intervention. Success relies on recognition of a deteriorating clinical condition, timely deployment of equipment/personnel and rapid execution. Given how infrequently it is performed, we sought to develop a large animal model of resternotomy to prepare ICU nurses and technicians at our low-volume cardiac surgery military centre. A porcine model of resternotomy was developed at the end of an already-scheduled trauma lab. Participants worked their way through a pre-planned simulation scenario, culminating in the need for resternotomy. Pre-simulation surveys assessing knowledge and comfort level with aspects of resternotomy were compared to post-simulation surveys. Participants improved their knowledge of resternotomy by 20.4% (P &lt; 0.0001; 14.7% for nurses and 26.9% for technicians). Improvements were seen in all aspects assessed relating to subjective comfort/preparedness of resternotomy. The model was an effective and realistic method to augment training of ICU staff about resternotomy. Costs associated with this model can be reduced when used in conjunction with large animal labs. This model should be used together with mannequin-based methods of resternotomy training to provide a realistic training environment and assessment of skills at capable institutions.

scholarly journals Impella RP versus pharmacologic vasoactive treatment in profound cardiogenic shock due to right ventricular failure: Unloading and end-organ perfusion in a large animal model

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
J Josiassen ◽  
OKL Helgestad ◽  
NLJ Udesen ◽  
A Banke ◽  
PH Frederiksen ◽  
...  
Keyword(s):  
Animal Model ◽  
Cardiogenic Shock ◽  
Oxygen Saturation ◽  
Treatment Strategies ◽  
Large Animal Model ◽  
Similar Degree ◽  
Large Animal ◽  
Organ Perfusion ◽  
Venous Oxygen Saturation ◽  
Cerebral Venous Oxygen Saturation

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation Unrestricted research grant from Abiomed Background No strong evidence exists regarding the treatment of cardiogenic shock (CS) caused by acute right ventricular (RV) failure which has mainly consisted of vasoactive drugs. There is expert agreement that treatment with the recently developed Impella RP is feasible, but no previous studies have compared vasoactive treatment strategies with the Impella RP in terms of cardiac unloading and end-organ perfusion. Hypothesis Treatment with the Impella RP device will be associated with lower RV myocardial workload (pressure-volume area) compared to vasoactive treatment strategies and can furthermore be achieved without compromising organ perfusion. Methods CS was induced by a stepwise injection of polyvinyl alcohol microspheres into the right coronary artery in twenty adult female Danish landrace pigs weighing 75-80 kg. After induction of CS, the pigs were allocated to one of the two interventions for 180 minutes: 1) vasoactive therapy comprised a continuous infusion of norepinephrine (0.1 µg/kg/min) for the first 30 minutes, supplemented by an infusion of milrinone (0.4 µg/kg/min) for the remaining 150 minutes or 2) immediate insertion of and treatment with the Impella RP.  The results are presented as median [Q1;Q3]. Results Treatment with the Impella RP was associated with a lower RV workload compared to the vasoactive group, while no difference was observed with regards to left ventricular workload among intervention groups, Figure 1. Renal venous oxygen saturation increased to a similar degree following both interventions compared to the state of CS. A trend towards a higher cerebral venous oxygen saturation was observed with norepinephrine compared to Impella RP (Impella RP 51 [47;61] % vs Norepinephrine 62 [57;71] % ; p = 0.07), which became significantly higher with the addition of milrinone (Impella RP 45 [32;63] % vs Norepinephrine +Milrinone 73 [66;81] %; p = 0.002). Conclusion In this large animal model of profound CS caused by predominantly RV failure the Impella RP unloaded the failing RV. The vasoactive treatment, however, caused a higher cerebral venous oxygen saturation, while both interventions increased renal venous oxygen saturation to a similar degree. Abstract Figure 1

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