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Yoganandan N, Shah A, Baisden J, Stemper B, Otterson M, Somberg L, Bass C, Salzar R, McMahon J, Chancey C, McEntire J. Matched-pair hybrid test paradigm for behind armor blunt trauma using an experimental animal model. Trauma Surg Acute Care Open 2024; 9:e001194. [PMID: 38860115 PMCID: PMC11163657 DOI: 10.1136/tsaco-2023-001194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 05/12/2024] [Indexed: 06/12/2024] Open
Abstract
Background The current behind armor blunt trauma (BABT) injury criterion uses a single penetration limit of 44 mm in Roma Plastilina clay and is not specific to thoracoabdominal regions. However, different regions in the human body have different injury tolerances. This manuscript presents a matched-pair hybrid test paradigm with different experimental models and candidate metrics to develop regional human injury criteria. Methods Live and cadaver swine were used as matched pair experimental models. An impactor simulating backface deformation profiles produced by body armor from military-relevant ballistics was used to deliver BABT loading to liver and lung regions in cadaver and live swine. Impact loading was characterized using peak accelerations and energy. For live swine, physiological parameters were monitored for 6 hours, animals were euthanized, and a detailed necropsy was done to identify injuries to skeletal structures, organs and soft tissues. A similar process was used to identify injuries to the cadaver swine for targeted thoracoabdominal regions. Results Two cadavers and one live swine were subjected to BABT impacts to the liver. One cadaver and one live swine were subjected to BABT impacts to the left lung. Injuries to both regions were similar at similar energies between the cadaver and live models. Conclusions Swine is an established animal for thoracoabdominal impact studies in automotive standards, although at lower insult levels. Similarities in BABT responses between cadaver and live swine allow for extending testing protocols to human cadavers and for the development of scaling relationships between animal and human cadavers, acting as a hybrid protocol between species and live and cadaver models. Injury tolerances and injury risk curves from live animals can be converted to human tolerances via structural scaling using these outcomes. The present experimental paradigm can be used to develop region-based BABT injury criteria, which are not currently available.
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Affiliation(s)
| | - Alok Shah
- Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jamie Baisden
- Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Brian Stemper
- Neurosurgery and Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Mary Otterson
- Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Lewis Somberg
- Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Cameron Bass
- Biomedical Engineering, Duke University, Durham, North Carolina, USA
| | - Robert Salzar
- Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Justin McMahon
- Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Carol Chancey
- Injury Biomechanics and Protection Group, USAARL, Fort Rucker, Alabama, USA
| | - Joseph McEntire
- Injury Biomechanics and Protection Group, USAARL, Fort Rucker, Alabama, USA
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Shen Z, Zhong Y, Wang Y, Zhu H, Liu R, Yu S, Zhang H, Wang M, Yang T, Zhang M. A computational approach to estimate postmortem interval using postmortem computed tomography of multiple tissues based on animal experiments. Int J Legal Med 2024; 138:1093-1107. [PMID: 37999765 DOI: 10.1007/s00414-023-03127-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 10/27/2023] [Indexed: 11/25/2023]
Abstract
The estimation of postmortem interval (PMI) is a complex and challenging problem in forensic medicine. In recent years, many studies have begun to use machine learning methods to estimate PMI. However, research combining postmortem computed tomography (PMCT) with machine learning models for PMI estimation is still in early stages. This study aims to establish a multi-tissue machine learning model for PMI estimation using PMCT data from various tissues. We collected PMCT data of seven tissues, including brain, eyeballs, myocardium, liver, kidneys, erector spinae, and quadriceps femoris from 10 rabbits after death. CT images were taken every 12 h until 192 h after death, and HU values were extracted from the CT images of each tissue as a dataset. Support vector machine, random forest, and K-nearest neighbors were performed to establish PMI estimation models, and after adjusting the parameters of each model, they were used as first-level classification to build a stacking model to further improve the PMI estimation accuracy. The accuracy and generalized area under the receiver operating characteristic curve of the multi-tissue stacking model were able to reach 93% and 0.96, respectively. Results indicated that PMCT detection could be used to obtain postmortem change of different tissue densities, and the stacking model demonstrated strong predictive and generalization abilities. This approach provides new research methods and ideas for the study of PMI estimation.
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Affiliation(s)
- Zefang Shen
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China
| | - Yue Zhong
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China
| | - Yucong Wang
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China
| | - Haibiao Zhu
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China
| | - Ran Liu
- Forensic Science Center of Beijing Huatong Junjian Science and Technology Company Limited, Beijing, 100016, China
| | - Shengnan Yu
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China
| | - Haidong Zhang
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China
| | - Min Wang
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China
| | - Tiantong Yang
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China.
| | - Mengzhou Zhang
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, No. 25 Xitucheng Road, Haidian District, Beijing, 100088, China.
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Andreis FR, Metcalfe B, Janjua TAM, Fazan VPS, Jensen W, Meijs S, Nielsen TGNDS. Morphology and morphometry of the ulnar nerve in the forelimb of pigs. Anat Histol Embryol 2024; 53:e12972. [PMID: 37715494 DOI: 10.1111/ahe.12972] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 08/24/2023] [Accepted: 09/09/2023] [Indexed: 09/17/2023]
Abstract
The knowledge of the morphology and morphometry of peripheral nerves is essential for developing neural interfaces and understanding nerve regeneration in basic and applied research. Currently, the most adopted animal model is the rat, even though recent studies have suggested that the neuroanatomy of large animal models is more comparable to humans. The present knowledge of the morphological structure of large animal models is limited; therefore, the present study aims to describe the morphological characteristics of the Ulnar Nerve (UN) in pigs. UN cross-sections were taken from seven Danish landrace pigs at three distinct locations: distal UN, proximal UN and at the dorsal cutaneous branch of the UN (DCBUN). The nerve diameter, fascicle diameter and number, number of fibres and fibre size were quantified. The UN diameter was larger in the proximal section compared to the distal segment and the DCBUN. The proximal branch also had a more significant number of fascicles (median: 15) than the distal (median: 10) and the DCBUN (median: 11) segments. Additionally, the mean fascicle diameter was smaller at the DCBUN (mean: 165 μm) than at the distal (mean: 197 μm) and proximal (mean: 199 μm) segments of the UN. Detailed knowledge of the microscopical structure of the UN in pigs is critical for further studies investigating neural interface designs and computational models of the peripheral nervous system.
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Affiliation(s)
- Felipe Rettore Andreis
- Department of Health Science and Technology, Center for Neuroplasticity and Pain (CNAP), Aalborg University, Aalborg, Denmark
| | - Benjamin Metcalfe
- Bath Institute for the Augmented Human, University of Bath, Bath, UK
| | - Taha Al Muhammadee Janjua
- Department of Health Science and Technology, Center for Neuroplasticity and Pain (CNAP), Aalborg University, Aalborg, Denmark
| | - Valéria Paula Sassoli Fazan
- Department of Surgery and Anatomy, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Winnie Jensen
- Department of Health Science and Technology, Center for Neuroplasticity and Pain (CNAP), Aalborg University, Aalborg, Denmark
| | - Suzan Meijs
- Department of Health Science and Technology, Center for Neuroplasticity and Pain (CNAP), Aalborg University, Aalborg, Denmark
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Hou J, Ness SS, Tschudi J, O’Farrell M, Veddegjerde R, Martinsen ØG, Tønnessen TI, Strand-Amundsen R. Assessment of Intestinal Ischemia-Reperfusion Injury Using Diffuse Reflectance VIS-NIR Spectroscopy and Histology. SENSORS (BASEL, SWITZERLAND) 2022; 22:9111. [PMID: 36501812 PMCID: PMC9738753 DOI: 10.3390/s22239111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/05/2022] [Accepted: 11/16/2022] [Indexed: 06/17/2023]
Abstract
A porcine model was used to investigate the feasibility of using VIS-NIR spectroscopy to differentiate between degrees of ischemia-reperfusion injury in the small intestine. Ten pigs were used in this study and four segments were created in the small intestine of each pig: (1) control, (2) full arterial and venous mesenteric occlusion for 8 h, (3) arterial and venous mesenteric occlusion for 2 h followed by reperfusion for 6 h, and (4) arterial and venous mesenteric occlusion for 4 h followed by reperfusion for 4 h. Two models were built using partial least square discriminant analysis. The first model was able to differentiate between the control, ischemic, and reperfused intestinal segments with an average accuracy of 99.2% with 10-fold cross-validation, and the second model was able to discriminate between the viable versus non-viable intestinal segments with an average accuracy of 96.0% using 10-fold cross-validation. Moreover, histopathology was used to investigate the borderline between viable and non-viable intestinal segments. The VIS-NIR spectroscopy method together with a PLS-DA model showed promising results and appears to be well-suited as a potentially real-time intraoperative method for assessing intestinal ischemia-reperfusion injury, due to its easy-to-use and non-invasive nature.
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Affiliation(s)
- Jie Hou
- Department of Physics, University of Oslo, Sem Sælands vei 24, 0371 Oslo, Norway
- Department of Clinical and Biomedical Engineering, Oslo University Hospital, 0424 Oslo, Norway
| | - Siri Schøne Ness
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway
| | - Jon Tschudi
- SINTEF AS, Smart Sensors and Microsystems, Forskningsveien 1, 0373 Oslo, Norway
| | - Marion O’Farrell
- SINTEF AS, Smart Sensors and Microsystems, Forskningsveien 1, 0373 Oslo, Norway
| | | | - Ørjan Grøttem Martinsen
- Department of Physics, University of Oslo, Sem Sælands vei 24, 0371 Oslo, Norway
- Department of Clinical and Biomedical Engineering, Oslo University Hospital, 0424 Oslo, Norway
| | - Tor Inge Tønnessen
- Department of Emergencies and Critical Care, Oslo University Hospital, 0424 Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway
| | - Runar Strand-Amundsen
- Department of Clinical and Biomedical Engineering, Oslo University Hospital, 0424 Oslo, Norway
- Sensocure AS, Langmyra 11, 3185 Skoppum, Norway
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Exploring Porcine Precision-Cut Kidney Slices as a Model for Transplant-Related Ischemia-Reperfusion Injury. TRANSPLANTOLOGY 2022. [DOI: 10.3390/transplantology3020015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Marginal donor kidneys are more likely to develop ischemia-reperfusion injury (IRI), resulting in inferior long-term outcomes. Perfusion techniques are used to attenuate IRI and improve graft quality. However, machine perfusion is still in its infancy, and more research is required for optimal conditions and potential repairing therapies. Experimental machine perfusion using porcine kidneys is a great way to investigate transplant-related IRI, but these experiments are costly and time-consuming. Therefore, an intermediate model to study IRI would be of great value. We developed a precision-cut kidney slice (PCKS) model that resembles ischemia-reperfusion and provides opportunities for studying multiple interventions simultaneously. Porcine kidneys were procured from a local slaughterhouse, exposed to 30 min of warm ischemia, and cold preserved. Subsequently, PCKS were prepared and incubated under various conditions. Adenosine triphosphate (ATP) levels and histological tissue integrity were assessed for renal viability and injury. Slicing did not influence tissue viability, and PCKS remained viable up to 72 h incubation with significantly increased ATP levels. Hypothermic and normothermic incubation led to significantly higher ATP levels than baseline. William’s medium E supplemented with Ciprofloxacin (and Amphotericin-B) provided the most beneficial condition for incubation of porcine PCKS. The porcine PCKS model can be used for studying transplant IRI.
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Small intestinal viability assessment using dielectric relaxation spectroscopy and deep learning. Sci Rep 2022; 12:3279. [PMID: 35228559 PMCID: PMC8885696 DOI: 10.1038/s41598-022-07140-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 02/14/2022] [Indexed: 11/09/2022] Open
Abstract
Intestinal ischemia is a serious condition where the surgeon often has to make important but difficult decisions regarding resections and resection margins. Previous studies have shown that 3 h (hours) of warm full ischemia of the small bowel followed by reperfusion appears to be the upper limit for viability in the porcine mesenteric ischemia model. However, the critical transition between 3 to 4 h of ischemic injury can be nearly impossible to distinguish intraoperatively based on standard clinical methods. In this study, permittivity data from porcine intestine was used to analyze the characteristics of various degrees of ischemia/reperfusion injury. Our results show that dielectric relaxation spectroscopy can be used to assess intestinal viability. The dielectric constant and conductivity showed clear differences between healthy, ischemic and reperfused intestinal segments. This indicates that dielectric parameters can be used to characterize different intestinal conditions. In addition, machine learning models were employed to classify viable and non-viable segments based on frequency dependent dielectric properties of the intestinal tissue, providing a method for fast and accurate intraoperative surgical decision-making. An average classification accuracy of 98.7% was obtained using only permittivity data measured during ischemia, and 96.2% was obtained with data measured during reperfusion. The proposed approach allows the surgeon to get accurate evaluation from the trained machine learning model by performing one single measurement on an intestinal segment where the viability state is questionable.
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Andreis FR, Metcalfe B, Janjua TAM, Jensen W, Meijs S, dos Santos Nielsen TGN. The Use of the Velocity Selective Recording Technique to Reveal the Excitation Properties of the Ulnar Nerve in Pigs. SENSORS (BASEL, SWITZERLAND) 2021; 22:58. [PMID: 35009601 PMCID: PMC8747393 DOI: 10.3390/s22010058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/02/2021] [Accepted: 12/16/2021] [Indexed: 06/14/2023]
Abstract
Decoding information from the peripheral nervous system via implantable neural interfaces remains a significant challenge, considerably limiting the advancement of neuromodulation and neuroprosthetic devices. The velocity selective recording (VSR) technique has been proposed to improve the classification of neural traffic by combining temporal and spatial information through a multi-electrode cuff (MEC). Therefore, this study investigates the feasibility of using the VSR technique to characterise fibre type based on the electrically evoked compound action potentials (eCAP) propagating along the ulnar nerve of pigs in vivo. A range of electrical stimulation parameters (amplitudes of 50 μA-10 mA and pulse durations of 100 μs, 500 μs, 1000 μs, and 5000 μs) was applied on a cutaneous and a motor branch of the ulnar nerve in nine Danish landrace pigs. Recordings were made with a 14 ring MEC and a delay-and-add algorithm was used to convert the eCAPs into the velocity domain. The results revealed two fibre populations propagating along the cutaneous branch of the ulnar nerve, with mean velocities of 55 m/s and 21 m/s, while only one dominant fibre population was found for the motor branch, with a mean velocity of 63 m/s. Because of its simplicity to provide information on the fibre selectivity and direction of propagation of nerve fibres, VSR can be implemented to advance the performance of the bidirectional control of neural prostheses and bioelectronic medicine applications.
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Affiliation(s)
- Felipe Rettore Andreis
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark; (T.A.M.J.); (W.J.); (S.M.); (T.G.N.d.S.N.)
| | - Benjamin Metcalfe
- Center for Biosensors, Bioelectronics and Biodevices (C3Bio), Department of Electronic & Electrical Engineering, University of Bath, Bath BA2 7AY, UK;
| | - Taha Al Muhammadee Janjua
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark; (T.A.M.J.); (W.J.); (S.M.); (T.G.N.d.S.N.)
| | - Winnie Jensen
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark; (T.A.M.J.); (W.J.); (S.M.); (T.G.N.d.S.N.)
| | - Suzan Meijs
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark; (T.A.M.J.); (W.J.); (S.M.); (T.G.N.d.S.N.)
| | - Thomas Gomes Nørgaard dos Santos Nielsen
- Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark; (T.A.M.J.); (W.J.); (S.M.); (T.G.N.d.S.N.)
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8
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Multimodal characterization of Yucatan minipig behavior and physiology through maturation. Sci Rep 2021; 11:22688. [PMID: 34811385 PMCID: PMC8608884 DOI: 10.1038/s41598-021-00782-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 10/13/2021] [Indexed: 01/11/2023] Open
Abstract
Brain injuries induced by external forces are particularly challenging to model experimentally. In recent decades, the domestic pig has been gaining popularity as a highly relevant animal model to address the pathophysiological mechanisms and the biomechanics associated with head injuries. Understanding cognitive, motor, and sensory aspects of pig behavior throughout development is crucial for evaluating cognitive and motor deficits after injury. We have developed a comprehensive battery of tests to characterize the behavior and physiological function of the Yucatan minipig throughout maturation. Behavioral testing included assessments of learning and memory, executive functions, circadian rhythms, gait analysis, and level of motor activity. We applied traditional behavioral apparatus and analysis methods, as well as state-of-the-art sensor technologies to report on motion and activity, and artificial intelligent approaches to analyze behavior. We studied pigs from 16 weeks old through sexual maturity at 35 weeks old. The results show multidimensional characterization of minipig behavior, and how it develops and changes with age. This animal model may capitulate the biomechanical consideration and phenotype of head injuries in the developing brain and can drive forward the field of understanding pathophysiological mechanisms and developing new therapies to accelerate recovery in children who have suffered head trauma.
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Ryu SW, Kim JS, Oh BS, Yu SY, Lee JS, Park SH, Kang SW, Lee J, Lee MK, Rhee MS, Jung H, Hur TY, Kim HB, Kim JK, Lee JH, Lee JH. Peptoniphilus faecalis sp. nov., isolated from swine faeces. Int J Syst Evol Microbiol 2021; 71. [PMID: 34125664 DOI: 10.1099/ijsem.0.004836] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
An obligately anaerobic, Gram-positive, non-motile, coccus-shaped bacterial strain designated AGMB00490T was isolated from swine faeces. 16S rRNA gene sequence-based phylogenetic analysis indicated that the isolate belongs to the genus Peptoniphilus and that the most closely related species is Peptoniphilus gorbachii WAL 10418T (=KCTC 5947T, 97.22 % 16S rRNA gene sequence similarity). Whole genome sequence analysis determined that the DNA G+C content of strain AGMB00490T was 31.2 mol% and moreover that the genome size and numbers of tRNA and rRNA genes were 2 129 517 bp, 34 and 10, respectively. Strain AGMB00490T was negative for oxidase and urease; positive for catalase, indole production, arginine arylamidase, leucine arylamidase, tyrosine arylamidase and histidine arylamidase; and weakly positive for phenylalanine arylamidase and glycine arylamidase. The major cellular fatty acids (>10 %) of the isolate were determined to be C16 : 0 and C18 : 1 ω9c. Strain AGMB00490T produced acetic acid as a major end product of metabolism. Accordingly, phylogenetic, physiologic and chemotaxonomic analyses revealed that strain AGMB00490T represents a novel species for which the name Peptoniphilus faecalis sp. nov. is proposed. The type strain is AGMB00490T (=KCTC 15944T=NBRC 114159T).
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Affiliation(s)
- Seoung Woo Ryu
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Ji-Sun Kim
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Byeong Seob Oh
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Seung Yeob Yu
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Jung-Sook Lee
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Seung-Hwan Park
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Se Won Kang
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Jiyoung Lee
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Mi-Kyung Lee
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Moon-Soo Rhee
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
| | - Hyunjung Jung
- National Institute of Animal Science, Cheonan 31000, Republic of Korea
| | - Tai-Young Hur
- National Institute of Animal Science, Cheonan 31000, Republic of Korea
| | - Hyeun Bum Kim
- Department of Animal Resources Science, Dankook University, Cheonan 31116, Republic of Korea
| | - Jae-Kyung Kim
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea
| | - Ju-Hoon Lee
- Department of Food and Animal Biotechnology, Department of Agricultural Biotechnology, Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Republic of Korea
| | - Ju Huck Lee
- Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea
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Short-Term Effects of Early Menopause on Adiposity, Fatty Acids Profile and Insulin Sensitivity of a Swine Model of Female Obesity. BIOLOGY 2020; 9:biology9090284. [PMID: 32932852 PMCID: PMC7565410 DOI: 10.3390/biology9090284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
Menopause strongly increases incidence and consequences of obesity and non-communicable diseases in women, with recent research suggesting a very early onset of changes in lipid accumulation, dyslipidemia, and insulin resistance. However, there is a lack of adequate preclinical models for its study. The present trial evaluated the usefulness of an alternative method to surgical ovariectomy, the administration of two doses of a GnRH analogue-protein conjugate (Vacsincel®), for inducing ovarian inactivity in sows used as preclinical models of obesity and menopause. All the sows treated with the compound developed ovarian stoppage after the second dose and, when exposed to obesogenic diets during the following three months, showed changes in the patterns of fat deposition, in the fatty acids profiles at the different tissues and in the plasma concentrations of fructosamine, urea, β-hydroxibutirate, and haptoglobin when compared to obese fed with the same diet but maintaining ovarian activity. Altogether, these results indicate that menopause early augments the deleterious effects induced by overfeeding and obesity on metabolic traits, paving the way for future research on physiopathology of these conditions and possible therapeutic targets using the swine model.
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Silva KAS, Emter CA. Large Animal Models of Heart Failure: A Translational Bridge to Clinical Success. JACC Basic Transl Sci 2020; 5:840-856. [PMID: 32875172 PMCID: PMC7452204 DOI: 10.1016/j.jacbts.2020.04.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 04/10/2020] [Indexed: 12/12/2022]
Abstract
Preclinical large animal models play a critical and expanding role in translating basic science findings to the development and clinical approval of novel cardiovascular therapeutics. This state-of-the-art review outlines existing methodologies and physiological phenotypes of several HF models developed in large animals. A comprehensive list of porcine, ovine, and canine models of disease are presented, and the translational importance of these studies to clinical success is highlighted through a brief overview of recent devices approved by the FDA alongside associated clinical trials and preclinical animal reports. Increasing the use of large animal models of HF holds significant potential for identifying new mechanisms underlying this disease and providing valuable information regarding the safety and efficacy of new therapies, thus, improving physiological and economical translation of animal research to the successful treatment of human HF. Preclinical large animal models of heart failure (HF) play a critical and expanding role in translating basic science findings to the development and clinical approval of novel therapeutics and devices. The complex combination of cardiovascular events and risk factors leading to HF has proved challenging for the development of new treatments for these patients. This state-of-the-art review presents historical and recent studies in porcine, ovine, and canine models of HF and outlines existing methodologies and physiological phenotypes. The translational importance of large animal studies to clinical success is also highlighted with an overview of recent devices approved by the Food and Drug Administration, together with preclinical HF animal studies used to aid both development and safety and/or efficacy testing. Increasing the use of large animal models of HF holds significant potential for identifying the novel mechanisms underlying the clinical condition and to improving physiological and economical translation of animal research to successfully treat human HF.
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Key Words
- AF, atrial fibrillation
- ECM, extracellular matrix
- EDP, end-diastolic pressure
- EF, ejection fraction
- FDA, Food and Drug Administration
- HF, heart failure
- HFpEF
- HFpEF, heart failure with preserved ejection fraction
- HFrEF
- HFrEF, heart failure with reduced ejection fraction
- I/R, ischemia/reperfusion
- IABP, intra-aortic balloon pump
- LAD, left anterior descending
- LCx, left circumflex
- LV, left ventricular
- MI, myocardial infarction
- PCI, percutaneous coronary intervention
- RV, right ventricular
- heart failure
- large animal model
- preclinical
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Affiliation(s)
| | - Craig A Emter
- Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri
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12
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Lipiski M, Eberhard M, Fleischmann T, Halvachizadeh S, Kolb B, Maisano F, Sauer M, Falk V, Emmert MY, Alkadhi H, Cesarovic N. Computed Tomography-based evaluation of porcine cardiac dimensions to assist in pre-study planning and optimized model selection for pre-clinical research. Sci Rep 2020; 10:6020. [PMID: 32265478 PMCID: PMC7138799 DOI: 10.1038/s41598-020-63044-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 03/24/2020] [Indexed: 12/25/2022] Open
Abstract
The pig (Sus Scrofa Domestica) is an accepted model for preclinical evaluation of prosthetic heart valves and trans-catheter implantation techniques. Understanding porcine cardiac dimensions through three-dimensional computed tomography (CT), increases preclinical study success, leading to higher cost efficiency and to the observance of the obligation to the 3 R principles. Cardiac CT images of twenty-four Swiss large white pigs were segmented; aortic root, mitral valve, pulmonary trunk, tricuspid valve, as well as the aorto-mitral angle and left atrial height were analyzed. Correlation coefficient (r) was calculated in relation to body weight. In Swiss large white pigs, valvular dimensions, length of the pulmonary artery and ascending aorta as well as left atrial height correlate with body weight. Coronary ostia heights and aorto-mitral angle size can be neglected in animal size selection; no changes were found for either of the two parameters with increasing body weight.
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Affiliation(s)
- Miriam Lipiski
- Division of Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
| | - Matthias Eberhard
- Institute for Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland
| | - Thea Fleischmann
- Division of Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Beate Kolb
- Institute for Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland
| | - Francesco Maisano
- Department of Cardiac Surgery, University Heart Center Zurich, Zurich, Switzerland
| | - Mareike Sauer
- Division of Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Volkmar Falk
- Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany.,Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Berlin, Germany.,Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Maximilian Y Emmert
- Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany.,Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Berlin, Germany
| | - Hatem Alkadhi
- Institute for Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland
| | - Nikola Cesarovic
- Division of Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
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13
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Poole DC, Copp SW, Colburn TD, Craig JC, Allen DL, Sturek M, O'Leary DS, Zucker IH, Musch TI. Guidelines for animal exercise and training protocols for cardiovascular studies. Am J Physiol Heart Circ Physiol 2020; 318:H1100-H1138. [PMID: 32196357 DOI: 10.1152/ajpheart.00697.2019] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Whole body exercise tolerance is the consummate example of integrative physiological function among the metabolic, neuromuscular, cardiovascular, and respiratory systems. Depending on the animal selected, the energetic demands and flux through the oxygen transport system can increase two orders of magnitude from rest to maximal exercise. Thus, animal models in health and disease present the scientist with flexible, powerful, and, in some instances, purpose-built tools to explore the mechanistic bases for physiological function and help unveil the causes for pathological or age-related exercise intolerance. Elegant experimental designs and analyses of kinetic parameters and steady-state responses permit acute and chronic exercise paradigms to identify therapeutic targets for drug development in disease and also present the opportunity to test the efficacy of pharmacological and behavioral countermeasures during aging, for example. However, for this promise to be fully realized, the correct or optimal animal model must be selected in conjunction with reproducible tests of physiological function (e.g., exercise capacity and maximal oxygen uptake) that can be compared equitably across laboratories, clinics, and other proving grounds. Rigorously controlled animal exercise and training studies constitute the foundation of translational research. This review presents the most commonly selected animal models with guidelines for their use and obtaining reproducible results and, crucially, translates state-of-the-art techniques and procedures developed on humans to those animal models.
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Affiliation(s)
- David C Poole
- Department of Kinesiology, Kansas State University, Manhattan, Kansas.,Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas
| | - Steven W Copp
- Department of Kinesiology, Kansas State University, Manhattan, Kansas
| | - Trenton D Colburn
- Department of Kinesiology, Kansas State University, Manhattan, Kansas
| | - Jesse C Craig
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Salt Lake City, Utah
| | - David L Allen
- Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado
| | - Michael Sturek
- Department of Anatomy, Cell Biology and Physiology, Indiana University, Indianapolis, Indiana
| | - Donal S O'Leary
- Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan
| | - Irving H Zucker
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Timothy I Musch
- Department of Kinesiology, Kansas State University, Manhattan, Kansas.,Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas
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14
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Tanihara F, Hirata M, Thi Nguyen N, Anh Le Q, Hirano T, Otoi T. Generation of viable PDX1 gene-edited founder pigs as providers of nonmosaics. Mol Reprod Dev 2020; 87:471-481. [PMID: 32166879 DOI: 10.1002/mrd.23335] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 03/02/2020] [Indexed: 11/08/2022]
Abstract
Pancreatic duodenal homeobox 1 (PDX1) is a crucial gene for pancreas development during the fetal period. PDX1-modified pigs have the potential to be used as a model of diabetes mellitus. However, the severe health problems caused by the PDX1 mutation limit phenotypic studies of PDX1-modified pigs as diabetes models. In this study, we generated PDX1-modified pigs by the CRISPR/Cas9 system introduced into zygotes via electroporation and investigated the mosaicism, phenotypes, and inheritance of the resulting pigs. After the embryo transfer of PDX1-modified zygotes, nine mutant piglets were delivered. Two piglets were apancreatic biallelic mutants. For the other seven piglets, the ratio of mutant alleles to total alleles was 17.5-79.7%. Two mutant piglets with high mutation rates (67.7% and 79.7%) exhibited hypoplasia of the pancreas, whereas the other five piglets were healthy. One of the male mutant piglets was further analyzed. The ejaculated semen from the pig contained PDX1-mutant spermatozoa and the pig showed normal reproductive ability. In conclusion, the frequency of the PDX1 mutation is presumed to relate to pancreas formation, and PDX1 mutant founder pigs generated from zygotes introduced to the CRISPR/Cas9 system can serve as providers of nonmosaics to contribute to medical research on diabetes mellitus.
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Affiliation(s)
- Fuminori Tanihara
- Laboratory of Animal Reproduction, Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima, Tokushima, Japan
| | - Maki Hirata
- Laboratory of Animal Reproduction, Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima, Tokushima, Japan
| | - Nhien Thi Nguyen
- Laboratory of Animal Reproduction, Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima, Tokushima, Japan
| | - Quynh Anh Le
- Laboratory of Animal Reproduction, Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima, Tokushima, Japan
| | - Takayuki Hirano
- Laboratory of Animal Reproduction, Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima, Tokushima, Japan
| | - Takeshige Otoi
- Laboratory of Animal Reproduction, Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima, Tokushima, Japan
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15
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Olver TD, Edwards JC, Jurrissen TJ, Veteto AB, Jones JL, Gao C, Rau C, Warren CM, Klutho PJ, Alex L, Ferreira-Nichols SC, Ivey JR, Thorne PK, McDonald KS, Krenz M, Baines CP, Solaro RJ, Wang Y, Ford DA, Domeier TL, Padilla J, Rector RS, Emter CA. Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure. JACC Basic Transl Sci 2019; 4:404-421. [PMID: 31312763 PMCID: PMC6610000 DOI: 10.1016/j.jacbts.2019.02.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/13/2019] [Accepted: 02/21/2019] [Indexed: 12/12/2022]
Abstract
The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF.
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Key Words
- AB, aortic-banded
- CON, control
- EDPVR, end-diastolic pressure−volume relationship
- EF, ejection fraction
- HF, heart failure
- HFpEF, heart failure with preserved ejection fraction
- HFrEF, heart failure with reduced ejection fraction
- IL1RL1, interleukin 1 receptor-like 1
- LV, left ventricle
- NF, nuclear factor
- PTX3, pentraxin-3
- WD, Western Diet
- cardio-metabolic disease
- heart failure
- integrative pathophysiology
- preclinical model of cardiovascular disease
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Affiliation(s)
- T. Dylan Olver
- Department of Biomedical Science, University of Missouri-Columbia, Columbia, Missouri
| | - Jenna C. Edwards
- Department of Biomedical Science, University of Missouri-Columbia, Columbia, Missouri
| | - Thomas J. Jurrissen
- Department of Nutrition and Exercise Physiology, University of Missouri-Columbia, Columbia, Missouri
| | - Adam B. Veteto
- Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri
| | - John L. Jones
- Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri
| | - Chen Gao
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Christoph Rau
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Chad M. Warren
- Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois
| | - Paula J. Klutho
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
| | - Linda Alex
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
| | | | - Jan R. Ivey
- Department of Biomedical Science, University of Missouri-Columbia, Columbia, Missouri
| | - Pamela K. Thorne
- Department of Biomedical Science, University of Missouri-Columbia, Columbia, Missouri
| | - Kerry S. McDonald
- Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
| | - Christopher P. Baines
- Department of Biomedical Science, University of Missouri-Columbia, Columbia, Missouri
- Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
| | - R. John Solaro
- Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois
| | - Yibin Wang
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - David A. Ford
- Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University- School of Medicine, St. Louis, Missouri
| | - Timothy L. Domeier
- Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri
| | - Jaume Padilla
- Department of Nutrition and Exercise Physiology, University of Missouri-Columbia, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
- Department of Child Health, University of Missouri-Columbia, Columbia, Missouri
| | - R. Scott Rector
- Department of Nutrition and Exercise Physiology, University of Missouri-Columbia, Columbia, Missouri
- Department of Medicine – University of Missouri-Columbia, Columbia, Missouri
- Research Service, Harry S Truman Memorial VA Hospital, University of Missouri-Columbia, Columbia, Missouri
| | - Craig A. Emter
- Department of Biomedical Science, University of Missouri-Columbia, Columbia, Missouri
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16
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Rini C, Roberts BC, Morel D, Klug R, Selvage B, Pettis RJ. Evaluating the Impact of Human Factors and Pen Needle Design on Insulin Pen Injection. J Diabetes Sci Technol 2019; 13:533-545. [PMID: 30880448 PMCID: PMC6501541 DOI: 10.1177/1932296819836987] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Limited published data exists quantifying the influence of human factors (HF) and pen needle (PN) design on delivery outcomes of pen injection systems. This preclinical in vivo study examines the impact of PN hub design and applied force against the skin during injection on needle penetration depth (NPD). METHOD To precisely locate injection depth, PN injections (20 µl; 2 IU, U-100 volume equivalent) of iodinated contrast agent were administered to the flank of Yorkshire swine across a range of clinically relevant application forces against the skin (0.25, 0.75, 1.25, and 2.0 lbf). The NPD, representing in vivo needle tip depth in SC tissue, from four 32 G × 4 mm PN devices (BD Nano™ 2nd Gen and three commercial posted-hub PN devices; n = 75/device/force, 1200 total) was measured by fluoroscopic imaging of the resulting depot. RESULTS The reengineered hub design more closely achieved the 4 mm target NPD with significantly less variability ( P = .006) than commercial posted-hub PN devices across the range of applied injection forces. Calculations of IM (intramuscular) injection risk completed through in silico probability model, using NPD and average human tissue thickness measurements, displayed a commensurate reduction (~2-8x) compared to conventional PN hub designs. CONCLUSIONS Quantifiable differences in injection depth were observed between identical labeled length PN devices indicating that hub design features, coupled with aspects of variable injection technique, may influence injection depth accuracy and consistency. The reengineered hub design may reduce the impact of unintended individual technique differences by improving target injection depth consistency and reducing IM injection potential.
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Affiliation(s)
- Christopher Rini
- BD Technologies and Innovation, Research Triangle Park, NC, USA
- Christopher Rini, MS, BD Technologies and Innovation, 21 Davis Dr, Research Triangle Park, NC 27709, USA.
| | | | | | - Rick Klug
- BD Technologies and Innovation, Research Triangle Park, NC, USA
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17
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H3K27me3 Depletion during Differentiation Promotes Myogenic Transcription in Porcine Satellite Cells. Genes (Basel) 2019; 10:genes10030231. [PMID: 30893875 PMCID: PMC6471710 DOI: 10.3390/genes10030231] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 02/23/2019] [Accepted: 03/11/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Porcine skeletal muscle satellite cells play important roles in myogenesis and muscle regeneration. Integrated analysis of transcriptome and histone modifications would reveal epigenomic roles in promoting myogenic differentiation in swine. METHODS Porcine satellite cells (PSCs) were isolated and in-vitro cultured from newborn piglets. RNA Sequencing (RNA-Seq) and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) experiments were performed using proliferating cells and terminal myotubes in order to interrogate the transcriptomic profiles, as well as the distribution of histone markers-H3K4me3, H3K27me3, and H3K27ac-and RNA polymerase II. RESULTS The study identified 917 differentially expressed genes during cell differentiation. The landscape of epigenetic marks was displayed on a genome-wide scale, which had globally shrunken. H3K27me3 reinforcement participated in obstructing the transcription of proliferation-related genes, while its depletion was closely related to the up-regulation of myogenic genes. Furthermore, the degree of H3K27me3 modification was dramatically reduced by 50%, and 139 myogenic genes were upregulated to promote cell differentiation. CONCLUSIONS The depletion of H3K27me3 was shown to promote porcine satellite cell differentiation through upregulating the transcription level of myogenic genes. Our findings in this study provide new insights of the epigenomic mechanisms occurring during myogenic differentiation, and shed light on chromatin states and the dynamics underlying myogenesis.
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18
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Intestinibaculum porci gen. nov., sp. nov., a new member of the family Erysipelotrichaceae isolated from the small intestine of a swine. J Microbiol 2019; 57:381-387. [PMID: 30796749 DOI: 10.1007/s12275-019-8631-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/21/2018] [Accepted: 12/21/2018] [Indexed: 12/11/2022]
Abstract
A strictly anaerobic, Gram-stain-positive, catalase-negative, non-motile, rod-shaped bacterium, designated SG0102T, was isolated from the small intestine of a swine. Optimal growth occurred at 37°C and pH 7.0. Furthermore, growth was observed in the presence of up to 3% (w/v) NaCl but not at salinity levels higher than 4%. The comparative analysis of 16S rRNA gene sequences showed that strain SG0102T was most closely related to Kandleria vitulina DSM 20405T (93.3%), followed by Catenibacterium mitsuokai KCTC 5053T (91.1%), Sharpea azabuensis KCTC 15217T (91.0%), and Eggerthia catenaformis DSM 5348T (89.6%). The average nucleotide identity values between strain SG0102T and related species, K. vitulina DSM 20405T, C. mitsuokai KCTC 5053T, S. azabuensis KCTC 15217T, and E. catenaformis DSM 5348T, were 71.0, 69.3, 70.0, and 69.2%, respectively. The phylogenetic analysis based on 16S rRNA gene sequence revealed that strain SG0102T belonged to the family Erysipelotrichaceae in the class Erysipelotrichia. The DNA G + C content of the strain SG0102T was 39.5 mol%. The major cellular fatty acids (> 10%) of strain SG0102T were C16:0, C16:0 dimethyl acetal, and C18:2ω9/12c. The cell wall peptidoglycan of strain SG0102T contained the meso-diaminopimelic acid. The strain SG0102T produced lactic acid as a major end product of fermentation. These distinct phenotypic and phylogenetic properties suggest that strain SG0102T represents a novel species in a novel genus of the family Erysipelotrichaceae, for which the name Intestinibaculum porci gen. nov. sp. nov. is proposed. The type strain is SG0102T (= KCTC 15725T = NBRC 113396T).
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19
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Kim E, Kim M, Hwang SU, Kim J, Lee G, Park YS, Hyun SH. Neural induction of porcine-induced pluripotent stem cells and further differentiation using glioblastoma-cultured medium. J Cell Mol Med 2019; 23:2052-2063. [PMID: 30609263 PMCID: PMC6378232 DOI: 10.1111/jcmm.14111] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 11/04/2018] [Accepted: 12/06/2018] [Indexed: 12/04/2022] Open
Abstract
Prior to transplantation, preclinical study of safety and efficacy of neural progenitor cells (NPCs) is needed. Therefore, it is important to generate an efficient in vitro platform for neural cell differentiation in large animal models such as pigs. In this study, porcine‐induced pluripotent stem cells (iPSCs) were seeded at high cell density to a neural induction medium containing the dual Sma‐ and Mad‐related protein (SMAD) inhibitors, a TGF‐β inhibitor and BMP4 inhibitor. The dSMADi‐derived NPCs showed NPC markers such as PLAG1, NESTIN and VIMENTIN and higher mRNA expression of Sox1 compared to the control. The mRNA expression of HOXB4 was found to significantly increase in the retinoic acid‐treated group. NPCs propagated in vitro and generated neurospheres that are capable of further differentiation in neurons and glial cells. Gliobalstoma‐cultured medium including injury‐related cytokines treated porcine iPSC‐NPCs survive well in vitro and showed more neuronal marker expression compared to standard control medium. Collectively, the present study developed an efficient method for production of neural commitment of porcine iPSCs into NPCs.
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Affiliation(s)
- Eunhye Kim
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Chungbuk, Korea.,Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and Collage of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Mirae Kim
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Chungbuk, Korea.,Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and Collage of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Seon-Ung Hwang
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Chungbuk, Korea.,Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and Collage of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Jongpil Kim
- Laboratory of Stem Cells and Cell Reprogramming, Department of Biomedical Engineering, Dongguk University, Seoul, Korea
| | - Gabsang Lee
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Young Seok Park
- Department of Neurosurgery, College of Medicine, Chungbuk National University Hospital, Chungbuk National University, Cheongju, Korea
| | - Sang-Hwan Hyun
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Chungbuk, Korea.,Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and Collage of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
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20
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Davidson S, Pretty C, Balmer J, Desaive T, Chase JG. Blood pressure waveform contour analysis for assessing peripheral resistance changes in sepsis. Biomed Eng Online 2018; 17:171. [PMID: 30458800 PMCID: PMC6245924 DOI: 10.1186/s12938-018-0603-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 11/09/2018] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND This paper proposes a methodology for helping bridge the gap between the complex waveform information frequently available in an intensive care unit and the simple, lumped values favoured for rapid clinical diagnosis and management. This methodology employs a simple waveform contour analysis approach to compare aortic, femoral and central venous pressure waveforms on a beat-by-beat basis and extract lumped metrics pertaining to the pressure drop and pressure-pulse amplitude attenuation as blood passes through the various sections of systemic circulation. RESULTS Validation encompasses a comparison between novel metrics and well-known, analogous clinical metrics such as mean arterial and venous pressures, across an animal model of induced sepsis. The novel metric Ofe → vc, the direct pressure offset between the femoral artery and vena cava, and the clinical metric, ΔMP, the difference between mean arterial and venous pressure, performed well. However, Ofe → vc reduced the optimal average time to sepsis detection after endotoxin infusion from 46.2 min for ΔMP to 11.6 min, for a slight increase in false positive rate from 1.8 to 6.2%. Thus, the novel Ofe → vc provided the best combination of specificity and sensitivity, assuming an equal weighting to both, of the metrics assessed. CONCLUSIONS Overall, the potential of these novel metrics in the detection of diagnostic shifts in physiological behaviour, here driven by sepsis, is demonstrated.
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Affiliation(s)
- Shaun Davidson
- Department of Mechanical Engineering, University of Canterbury, Christchurch, New Zealand.
| | - Chris Pretty
- Department of Mechanical Engineering, University of Canterbury, Christchurch, New Zealand
| | - Joel Balmer
- Department of Mechanical Engineering, University of Canterbury, Christchurch, New Zealand
| | - Thomas Desaive
- GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - J Geoffrey Chase
- Department of Mechanical Engineering, University of Canterbury, Christchurch, New Zealand
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21
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Ahmad F, Prabhu RJ, Liao J, Soe S, Jones MD, Miller J, Berthelson P, Enge D, Copeland KM, Shaabeth S, Johnston R, Maconochie I, Theobald PS. Biomechanical properties and microstructure of neonatal porcine ventricles. J Mech Behav Biomed Mater 2018; 88:18-28. [PMID: 30118921 DOI: 10.1016/j.jmbbm.2018.07.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 06/26/2018] [Accepted: 07/27/2018] [Indexed: 12/29/2022]
Abstract
Neonatal heart disorders represent a major clinical challenge, with congenital heart disease alone affecting 36,000 new-borns annually within the European Union. Surgical intervention to restore normal function includes the implantation of synthetic and biological materials; however, a lack of experimental data describing the mechanical behaviour of neonatal cardiac tissue is likely to contribute to the relatively poor short- and long-term outcome of these implants. This study focused on characterising the mechanical behaviour of neonatal cardiac tissue using a porcine model, to enhance the understanding of how this differs to the equivalent mature tissue. The biomechanical properties of neonatal porcine cardiac tissue were characterised by uniaxial tensile, biaxial tensile, and simple shear loading modes, using samples collected from the anterior and posterior walls of the right and left ventricles. Histological images were prepared using Masson's trichrome staining, to enable assessment of the microstructure and correlation with tissue behaviour. The mechanical tests demonstrated that the neonatal cardiac tissue is non-linear, anisotropic, viscoelastic and heterogeneous. Our data provide a baseline describing the biomechanical behaviour of immature porcine cardiac tissue. Comparison with published data also indicated that the neonatal porcine cardiac tissue exhibits one-half the stiffness of mature porcine tissue in uniaxial extension testing, one-third in biaxial extension testing, and one-fourth stiffness in simple shear testing; hence, it provides an indication as to the relative change in characteristics associated with tissue maturation. These data may prove valuable to researchers investigating neonatal cardiac mechanics.
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Affiliation(s)
| | - Ra J Prabhu
- Centre for Advanced Vehicular Systems and Department of Biological Engineering, Mississippi State University, USA
| | - Jun Liao
- Centre for Advanced Vehicular Systems and Department of Biological Engineering, Mississippi State University, USA; Department of Bioengineering, The University of Texas at Arlington, USA.
| | - Shwe Soe
- School of Engineering, Cardiff University, UK
| | | | - Jonathan Miller
- Centre for Advanced Vehicular Systems and Department of Biological Engineering, Mississippi State University, USA
| | - Parker Berthelson
- Centre for Advanced Vehicular Systems and Department of Biological Engineering, Mississippi State University, USA
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22
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Strand-Amundsen RJ, Reims HM, Reinholt FP, Ruud TE, Yang R, Høgetveit JO, Tønnessen TI. Ischemia/reperfusion injury in porcine intestine - Viability assessment. World J Gastroenterol 2018; 24:2009-2023. [PMID: 29760544 PMCID: PMC5949714 DOI: 10.3748/wjg.v24.i18.2009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 04/20/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate viability assessment of segmental small bowel ischemia/reperfusion in a porcine model.
METHODS In 15 pigs, five or six 30-cm segments of jejunum were simultaneously made ischemic by clamping the mesenteric arteries and veins for 1 to 16 h. Reperfusion was initiated after different intervals of ischemia (1-8 h) and subsequently monitored for 5-15 h. The intestinal segments were regularly photographed and assessed visually and by palpation. Intraluminal lactate and glycerol concentrations were measured by microdialysis, and samples were collected for light microscopy and transmission electron microscopy. The histological changes were described and graded.
RESULTS Using light microscopy, the jejunum was considered as viable until 6 h of ischemia, while with transmission electron microscopy the ischemic muscularis propria was considered viable until 5 h of ischemia. However, following ≥ 1 h of reperfusion, only segments that had been ischemic for ≤ 3 h appeared viable, suggesting a possible upper limit for viability in the porcine mesenteric occlusion model. Although intraluminal microdialysis allowed us to closely monitor the onset and duration of ischemia and the onset of reperfusion, we were unable to find sufficient level of association between tissue viability and metabolic markers to conclude that microdialysis is clinically relevant for viability assessment. Evaluation of color and motility appears to be poor indicators of intestinal viability.
CONCLUSION Three hours of total ischemia of the small bowel followed by reperfusion appears to be the upper limit for viability in this porcine mesenteric ischemia model.
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Affiliation(s)
- Runar J Strand-Amundsen
- Department of Clinical and Biomedical Engineering, Oslo University Hospital, Oslo 0424, Norway
- Department of Physics, University of Oslo, Oslo 0316, Norway
| | - Henrik M Reims
- Department of Pathology, Oslo University Hospital, Oslo 0424, Norway
| | - Finn P Reinholt
- Department of Pathology, Oslo University Hospital, Oslo 0424, Norway
| | - Tom E Ruud
- Institute for Surgical Research, Oslo University Hospital, Oslo 0424, Norway
- Department of Surgery, Baerum Hospital, Vestre Viken Hospital Trust, Drammen 3004, Norway
| | - Runkuan Yang
- Department of Emergencies and Critical Care, Oslo University Hospital, Oslo 0424, Norway
| | - Jan O Høgetveit
- Department of Clinical and Biomedical Engineering, Oslo University Hospital, Oslo 0424, Norway
- Department of Physics, University of Oslo, Oslo 0316, Norway
| | - Tor I Tønnessen
- Department of Emergencies and Critical Care, Oslo University Hospital, Oslo 0424, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo 0424, Norway
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23
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Kim H, Park H, Lee SJ. Effective method for drug injection into subcutaneous tissue. Sci Rep 2017; 7:9613. [PMID: 28852051 PMCID: PMC5575294 DOI: 10.1038/s41598-017-10110-w] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 08/03/2017] [Indexed: 11/09/2022] Open
Abstract
Subcutaneous injection of drug solution is widely used for continuous and low dose drug treatment. Although the drug injections have been administered for a long time, challenges in the design of injection devices are still needed to minimize the variability, pain, or skin disorder by repeated drug injections. To avoid these adverse effects, systematic study on the effects of injection conditions should be conducted to improve the predictability of drug effect. Here, the effects of injection conditions on the drug permeation in tissues were investigated using X-ray imaging technique which provides real-time images of drug permeation with high spatial resolution. The shape and concentration distribution of the injected drug solution in the porcine subcutaneous and muscle tissues are visualized. Dynamic movements of the wetting front (WF) and temporal variations of water contents in the two tissues are quantitatively analyzed. Based on the quantitative analysis of the experimental data, the permeability of drug solution through the tissues are estimated according to permeation direction, injection speed, and tissue. The present results would be helpful for improving the performance of drug injection devices and for predicting the drug efficacy in tissues using biomedical simulation.
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Affiliation(s)
- Hyejeong Kim
- Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Gyeongsangbuk, Republic of Korea
| | - Hanwook Park
- Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Gyeongsangbuk, Republic of Korea
| | - Sang Joon Lee
- Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Gyeongsangbuk, Republic of Korea.
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24
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Detterbeck A, Hofmeister M, Haddad D, Weber D, Schmid M, Hölzing A, Zabler S, Hofmann E, Hiller KH, Jakob P, Engel J, Hiller J, Hirschfelder U. Determination of the mesio-distal tooth width via 3D imaging techniques with and without ionizing radiation: CBCT, MSCT, and µCT versus MRI. Eur J Orthod 2017; 39:310-319. [PMID: 27365182 DOI: 10.1093/ejo/cjw047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Objective The purpose of this study was to estimate the feasibility and accuracy of mesio-distal width measurements with magnetic resonance imaging (MRI) in comparison to conventional 3D imaging techniques [multi-slice CT (MSCT), cone-beam CT (CBCT), and µCT]. The measured values of the tooth widths were compared to each other to estimate the amount of radiation necessary to enable orthodontic diagnostics. Material and Methods Two pig skulls were measured with MSCT, CBCT, µCT, and MRI. Three different judges were asked to determine the mesio-distal tooth width of 14 teeth in 2D tomographic images and in 3D segmented images via a virtual ruler in every imaging dataset. Results Approximately 19% (27/140) of all test points in 2D tomographic slice images and 12% (17/140) of the test points in 3D segmented images showed a significant difference (P ≤ 0.05). The largest significant difference was 1.6mm (P < 0.001). There were fewer significant differences in the measurement of the tooth germs than in erupted teeth. Conclusions Measurement of tooth width by MRI seems to be clinically equivalent to the conventional techniques (CBCT and MSCT). Tooth germs are better illustrated than erupted teeth on MRI. Three-dimensional segmented images offer only a slight advantage over 2D tomographic slice images. MRI, which avoids radiation, is particularly appealing in adolescents if these data can be corroborated in further studies.
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Affiliation(s)
- Andreas Detterbeck
- Department of Orthodontics and Orofacial Orthopaedics, Universitätsklinikum Erlangen, Germany
| | - Michael Hofmeister
- Department of Orthodontics and Orofacial Orthopaedics, Universitätsklinikum Erlangen, Germany
| | - Daniel Haddad
- MRB Research Center for Magnetic-Resonance-Bavaria, Würzburg, Germany.,Fraunhofer Development Center X-Ray Technology EZRT, A Division of Fraunhofer Institute for Integrated Circuits IIS, Department Magnetic Resonance and X-Ray Imaging, Würzburg, Germany
| | - Daniel Weber
- MRB Research Center for Magnetic-Resonance-Bavaria, Würzburg, Germany.,Fraunhofer Development Center X-Ray Technology EZRT, A Division of Fraunhofer Institute for Integrated Circuits IIS, Department Magnetic Resonance and X-Ray Imaging, Würzburg, Germany
| | - Matthias Schmid
- Institute of Medical Biometrics, Informatics and Epidemiology, University of Bonn, Germany
| | - Astrid Hölzing
- Fraunhofer Institute for Integrated Circuits, Project Group NanoCT Systems, Würzburg, Germany
| | - Simon Zabler
- Fraunhofer Institute for Integrated Circuits, Project Group NanoCT Systems, Würzburg, Germany
| | - Elisabeth Hofmann
- Department of Orthodontics and Orofacial Orthopaedics, Universitätsklinikum Erlangen, Germany
| | - Karl-Heinz Hiller
- MRB Research Center for Magnetic-Resonance-Bavaria, Würzburg, Germany.,Fraunhofer Development Center X-Ray Technology EZRT, A Division of Fraunhofer Institute for Integrated Circuits IIS, Department Magnetic Resonance and X-Ray Imaging, Würzburg, Germany
| | - Peter Jakob
- MRB Research Center for Magnetic-Resonance-Bavaria, Würzburg, Germany.,Fraunhofer Development Center X-Ray Technology EZRT, A Division of Fraunhofer Institute for Integrated Circuits IIS, Department Magnetic Resonance and X-Ray Imaging, Würzburg, Germany
| | - Jens Engel
- Fraunhofer Institute for Integrated Circuits, Project Group NanoCT Systems, Würzburg, Germany
| | - Jochen Hiller
- Fraunhofer Institute for Integrated Circuits, Application Center for CT in Metrology, Deggendorf, Germany
| | - Ursula Hirschfelder
- Department of Orthodontics and Orofacial Orthopaedics, Universitätsklinikum Erlangen, Germany
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25
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Ontogeny of Sex-Related Differences in Foetal Developmental Features, Lipid Availability and Fatty Acid Composition. Int J Mol Sci 2017; 18:ijms18061171. [PMID: 28561768 PMCID: PMC5485995 DOI: 10.3390/ijms18061171] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 05/05/2017] [Accepted: 05/25/2017] [Indexed: 12/18/2022] Open
Abstract
Sex-related differences in lipid availability and fatty acid composition during swine foetal development were investigated. Plasma cholesterol and triglyceride concentrations in the mother were strongly related to the adequacy or inadequacy of foetal development and concomitant activation of protective growth in some organs (brain, heart, liver and spleen). Cholesterol and triglyceride availability was similar in male and female offspring, but female foetuses showed evidence of higher placental transfer of essential fatty acids and synthesis of non-essential fatty acids in muscle and liver. These sex-related differences affected primarily the neutral lipid fraction (triglycerides), which may lead to sex-related postnatal differences in energy partitioning. These results illustrate the strong influence of the maternal lipid profile on foetal development and homeorhesis, and they confirm and extend previous reports that female offspring show better adaptive responses to maternal malnutrition than male offspring. These findings may help guide dietary interventions to ensure adequate fatty acid availability for postnatal development.
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26
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Ding S, Wang F, Liu Y, Li S, Zhou G, Hu P. Characterization and isolation of highly purified porcine satellite cells. Cell Death Discov 2017; 3:17003. [PMID: 28417015 PMCID: PMC5385392 DOI: 10.1038/cddiscovery.2017.3] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 12/07/2016] [Accepted: 12/29/2016] [Indexed: 12/20/2022] Open
Abstract
Pig is an important food source and an excellent system to model human diseases. Careful characterization of the swine skeletal muscle stem cells (satellite cells) will shed lights on generation of swine skeletal muscle disease model and efficient production of porcine meat for the food industry. Paired box protein 7 (Pax7) is a highly conserved transcription factor shared by satellite cells from various species. However, the sequence of Pax7 has not been characterized in pig. The lack of method to isolate highly purified satellite cells hinders the thorough characterization of the swine satellite cells. Here we found molecular markers for swine satellite cells and revealed that the porcine satellite cells were heterogeneous in various pieces of skeletal muscle. We further developed a method to isolate highly purified satellite cells directly from porcine muscles using fluorescence-activated cell sorting. We next characterized the proliferation and differentiation abilities of isolated satellite cells in vitro; and found that long-term culturing of satellite cells in vitro led to stemness loss.
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Affiliation(s)
- Shijie Ding
- Key Laboratory of Meat Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.,State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Fei Wang
- State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.,University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Yan Liu
- State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Sheng Li
- State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Guanghong Zhou
- Key Laboratory of Meat Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Ping Hu
- State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
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27
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Li Y, Wei H, Li F, Duan Y, Guo Q, Yin Y. Effects of Low-Protein Diets Supplemented with Branched-Chain Amino Acid on Lipid Metabolism in White Adipose Tissue of Piglets. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:2839-2848. [PMID: 28296401 DOI: 10.1021/acs.jafc.7b00488] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
This study evaluated the effect of branched-chain amino acid (BCAA) supplementation in low-protein diets on lipid metabolism in dorsal subcutaneous adipose (DSA), abdominal subcutaneous adipose (ASA), and perirenal adipose (PRA) tissues. A total of 24 piglets were allotted to four treatments, and each group was fed the adequate protein (AP) diet, low-protein (LP) diet, LP diet supplemented with BCAA (LP + B), or LP diet supplemented with twice BCAA (LP + 2B). Serum concentrations of leptin in the BCAA-supplemented treatments were higher (P < 0.01) than in the AP treatment, but lower (P < 0.01) than in the LP treatment. In DSA, the mRNA and protein levels for lipogenic-related genes were highest in the LP treatment and lowest in the LP + 2B treatment. However, in ASA and PRA, the expression levels for those genes were significantly elevated in the LP + 2B treatment. In conclusion, BCAA supplementation could alter the body fat condition, and this effect was likely modulated by the expression of lipid metabolic regulators in DSA, ASA, and PRA in a depot-specific manner.
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Affiliation(s)
- Yinghui Li
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences , Changsha, Hunan 410125, China
- University of Chinese Academy of Sciences , Beijing 100039, China
| | - Hongkui Wei
- College of Animal Sciences, Huazhong Agricultural University , Wuhan, Hubei 430070, China
| | - Fengna Li
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences , Changsha, Hunan 410125, China
- Hunan Co-Innovation Center of Animal Production Safety, CICAPS; Hunan Collaborative Innovation Center for Utilization of Botanical Functional Ingredients , Changsha, Hunan 410128, China
| | - Yehui Duan
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences , Changsha, Hunan 410125, China
- University of Chinese Academy of Sciences , Beijing 100039, China
| | - Qiuping Guo
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences , Changsha, Hunan 410125, China
- University of Chinese Academy of Sciences , Beijing 100039, China
| | - Yulong Yin
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences , Changsha, Hunan 410125, China
- Laboratory of Animal Nutrition and Human Health, School of Biology, Hunan Normal University , Changsha, Hunan 410018, China
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28
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Olver TD, Klakotskaia D, Ferguson BS, Hiemstra JA, Schachtman TR, Laughlin MH, Emter CA. Carotid Artery Vascular Mechanics Serve as Biomarkers of Cognitive Dysfunction in Aortic-Banded Miniature Swine That Can Be Treated With an Exercise Intervention. J Am Heart Assoc 2016; 5:JAHA.116.003248. [PMID: 27207966 PMCID: PMC4889197 DOI: 10.1161/jaha.116.003248] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Cognitive impairment in the setting of heart failure with preserved ejection fraction remains poorly understood. Using aortic‐banded miniature swine displaying pathological features of human heart failure with preserved ejection fraction, we tested the hypothesis that increased carotid artery stiffness and altered carotid blood flow control are associated with impaired memory independent of decreased cardiac output. Furthermore, we hypothesized that chronic exercise prevents carotid artery vascular restructuring and preserves normal blood flow control and cognition in heart failure with preserved ejection fraction. Methods and Results Yucatan pigs aged 8 months were divided into 3 groups: control (n=7), aortic‐banded sedentary (n=7), and aortic‐banded exercise trained (n=7). At 6 months following aortic‐banded or control conditions, memory was evaluated using a spatial hole‐board task. Carotid artery vascular mechanics and blood flow were assessed at rest, and blood flow control was examined during transient vena cava occlusion. Independent of decreased cardiac output, the aortic‐banded group exhibited impaired memory that was associated with carotid artery vascular stiffening, elevated carotid artery vascular resistance, and exaggerated reductions in carotid artery blood flow during vena cava occlusion. Chronic exercise augmented memory scores, normalized blood flow control, and improved indices of carotid artery vascular stiffening. Indices of vascular stiffening were significantly correlated with average memory score. Conclusions Carotid artery stiffness and altered vasomotor control correlate with impaired cognition independent of cardiac systolic dysfunction. Carotid artery vascular mechanics may serve as a biomarker for vascular cognitive impairment in heart failure with preserved ejection fraction. Chronic low‐intensity exercise reduces vascular stiffening and improves cognition, highlighting the utility of exercise therapy for treating vascular cognitive impairment in heart failure with preserved ejection fraction.
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Affiliation(s)
- T Dylan Olver
- Department of Biomedical Sciences, University of Missouri, Columbia, MO
| | - Diana Klakotskaia
- Department of Psychological Sciences, University of Missouri, Columbia, MO
| | - Brian S Ferguson
- Department of Biomedical Sciences, University of Missouri, Columbia, MO
| | | | - Todd R Schachtman
- Department of Psychological Sciences, University of Missouri, Columbia, MO
| | - M Harold Laughlin
- Department of Biomedical Sciences, University of Missouri, Columbia, MO Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO
| | - Craig A Emter
- Department of Biomedical Sciences, University of Missouri, Columbia, MO
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29
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Pharmacokinetics of heroin and its metabolites in vitreous humor and blood in a living pig model. Forensic Toxicol 2016; 34:277-285. [PMID: 27660664 PMCID: PMC5018035 DOI: 10.1007/s11419-016-0315-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 03/19/2016] [Indexed: 11/29/2022]
Abstract
Vitreous humor (VH) is an alternative matrix for drug analysis in forensic toxicology. However, little is known about the distribution of xenobiotics, such as opioids, into VH in living organisms. The aim of this study was to simultaneously measure heroin and metabolite concentrations in blood and VH after injection of heroin in a living pig model. Six pigs were under non-opioid anesthesia during the surgical operation and experiment. Ocular microdialysis was used to acquire dialysate from VH, and a venous catheter was used for blood sampling. Twenty milligrams of heroin was injected intravenously with subsequent sampling of blood and dialysate for 6 h. The samples were analyzed by ultra-performance liquid chromatography–tandem mass spectrometry. Heroin was not detected in VH; 6-monoacetylmorphine (6-MAM) and morphine were first detected in VH after 60 min. The morphine concentration in VH thereafter increased throughout the experimental period. For 6-MAM, Cmax was reached after 230 min in VH. In blood, 6-MAM reached Cmax after 0.5 min, with a subsequent biphasic elimination phase. The blood and VH 6-MAM concentrations reached equilibrium after 2 h. In blood, morphine reached Cmax after 4.3 min, with a subsequent slower elimination than 6-MAM. The blood and VH morphine concentrations were in equilibrium about 6 h after injection of heroin. In conclusion, both 6-MAM and morphine showed slow transport into VH; detection of 6-MAM in VH did not necessarily reflect a recent intake of heroin. Because postmortem changes are expected to be small in VH, these experimental results could assist the interpretation of heroin deaths.
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30
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Li Y, Wei H, Li F, Chen S, Duan Y, Guo Q, Liu Y, Yin Y. Supplementation of branched-chain amino acids in protein-restricted diets modulates the expression levels of amino acid transporters and energy metabolism associated regulators in the adipose tissue of growing pigs. ACTA ACUST UNITED AC 2016; 2:24-32. [PMID: 29767034 PMCID: PMC5940986 DOI: 10.1016/j.aninu.2016.01.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 01/29/2016] [Accepted: 01/31/2016] [Indexed: 12/17/2022]
Abstract
This experiment was conducted to investigate the effects of branched-chain amino acids (BCAA) supplemented in protein-restricted diets on the growth performance and the expression profile of amino acid transporters and energy metabolism related regulators in the white adipose tissue (WAT) of different regional depots including dorsal subcutaneous adipose (DSA) and abdominal subcutaneous adipose (ASA). A total of 24 crossbred barrows (7.40 ± 0.70 kg) were randomly divided into 4 groups and were fed the following isocaloric diets for 33 days: 1) a recommended adequate protein diet (AP, 20% CP, as a positive control); 2) a low protein diet (LP, 17% CP); 3) the LP diet supplemented with BCAA (LP + B, 17% CP) to reach the same level of the AP diet group; 4) the LP diet supplemented with 2 times the amount of BCAA (LP + 2B, 17% CP). The daily gain and daily feed intake of the LP diet group were the lowest among all the treatments (P < 0.01). The feed conversion was improved markedly in the group of LP + B compared with the LP diet group (P < 0.05). No significant difference was noted for the serum biochemical parameter concentrations of glucose, triglyceride, nonesterified fatty acid and insulin among the groups (P > 0.05). Moreover, BCAA supplementation down-regulated the expression levels of amino acid transporters including L-type amino acid transporter 1 and sodium-coupled neutral amino acid transporter 2 in DSA, but up-regulated the expression level of L-type amino acid transporter 4 in ASA (P < 0.05). Meanwhile, the energy sensor AMP-activated protein kinase α was activated in the DSA of pigs fed LP diet and in the ASA of the pigs fed AP or LP + 2B diets (P < 0.05). The mRNA expression profile of the selected mitochondrial component and mitochondrial biogenesis associated regulators in DSA and ASA also responded differently to dietary BCAA supplementation. These results suggested that the growth performance of growing pigs fed protein restricted diets supplemented with BCAA could catch up to that of the pigs fed AP diets. The results also partly demonstrated that the regulation mechanisms of BCAA are different in the adipose tissues of different depots.
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Affiliation(s)
- Yinghui Li
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Hongkui Wei
- College of Animal Sciences, Huazhong Agricultural University, Wuhan 430070, China
| | - Fengna Li
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- Hunan Co-Innovation Center of Animal Production Safety (CICAPS), Changsha 410128, China
- Corresponding authors.
| | - Shuai Chen
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yehui Duan
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Qiuping Guo
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yingying Liu
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yulong Yin
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- Changsha Lvye Biotechnology Limited Company Academician Expert Workstation, Changsha 410126, China
- Hang Zhou King Techina Limited Company Academician Expert Workstation, Hangzhou 311107, China
- Corresponding authors.
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31
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Bishop JH, Fox JR, Maple R, Loretan C, Badger GJ, Henry SM, Vizzard MA, Langevin HM. Ultrasound Evaluation of the Combined Effects of Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model. PLoS One 2016; 11:e0147393. [PMID: 26820883 PMCID: PMC4731465 DOI: 10.1371/journal.pone.0147393] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 01/04/2016] [Indexed: 12/15/2022] Open
Abstract
The persistence of back pain following acute back "sprains" is a serious public health problem with poorly understood pathophysiology. The recent finding that human subjects with chronic low back pain (LBP) have increased thickness and decreased mobility of the thoracolumbar fascia measured with ultrasound suggest that the fasciae of the back may be involved in LBP pathophysiology. This study used a porcine model to test the hypothesis that similar ultrasound findings can be produced experimentally in a porcine model by combining a local injury of fascia with movement restriction using a "hobble" device linking one foot to a chest harness for 8 weeks. Ultrasound measurements of thoracolumbar fascia thickness and shear plane mobility (shear strain) during passive hip flexion were made at the 8 week time point on the non-intervention side (injury and/or hobble). Injury alone caused both an increase in fascia thickness (p = .007) and a decrease in fascia shear strain on the non-injured side (p = .027). Movement restriction alone did not change fascia thickness but did decrease shear strain on the non-hobble side (p = .024). The combination of injury plus movement restriction had additive effects on reducing fascia mobility with a 52% reduction in shear strain compared with controls and a 28% reduction compared to movement restriction alone. These results suggest that a back injury involving fascia, even when healed, can affect the relative mobility of fascia layers away from the injured area, especially when movement is also restricted.
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Affiliation(s)
- James H. Bishop
- Department of Neurological Sciences, University of Vermont, Burlington, Vermont, United States of America
| | - James R. Fox
- Department of Neurological Sciences, University of Vermont, Burlington, Vermont, United States of America
| | - Rhonda Maple
- Department of Neurological Sciences, University of Vermont, Burlington, Vermont, United States of America
| | - Caitlin Loretan
- Department of Neurological Sciences, University of Vermont, Burlington, Vermont, United States of America
| | - Gary J. Badger
- Department of Medical Biostatistics, University of Vermont, Burlington, Vermont, United States of America
| | - Sharon M. Henry
- Department of Rehabilitation and Movement Science, University of Vermont, Burlington, Vermont, United States of America
| | - Margaret A. Vizzard
- Department of Neurological Sciences, University of Vermont, Burlington, Vermont, United States of America
| | - Helene M. Langevin
- Department of Neurological Sciences, University of Vermont, Burlington, Vermont, United States of America
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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32
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Abstract
The prevalence of heart failure is expected to increase almost 50% in the next 15 years because of aging of the general population, an increased frequency of comorbidities, and an improved survival following cardiac events. Conventional treatments for heart failure have remained largely static over the past 20 years, illustrating the pressing need for the discovery of novel therapeutic agents for this patient population. Given the heterogeneous nature of heart failure, it is important to specifically define the cellular mechanisms in the heart that drive the patient's symptoms, particularly when considering new treatment strategies. This report highlights the latest research efforts, as well as the possible pitfalls, in cardiac disease translational research and discusses future questions and considerations needed to advance the development of new heart failure therapies. In particular, we discuss cardiac remodeling and the translation of animal work to humans and how advancements in our understanding of these concepts relative to disease are central to new discoveries that can improve cardiovascular health.
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Affiliation(s)
- Michael S Kapiloff
- Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Craig A Emter
- Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, MO, USA
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Davidson SM, Kannangara DO, Pretty CG, Kamoi S, Pironet A, Desaive T, Chase JG. Modelling of the nonlinear end-systolic pressure-volume relation and volume-at-zero-pressure in porcine experiments. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2016; 2015:6544-7. [PMID: 26737792 DOI: 10.1109/embc.2015.7319892] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The End-Systolic Pressure-Volume Relation (ESPVR) is generally modelled as a linear relationship between P and V as cardiac reflexes, such as the baroreflex, are typically suppressed in experiments. However, ESPVR has been observed to behave in a curvilinear fashion when cardiac reflexes are not suppressed, suggesting the curvilinear function may be more clinically appropriate. Data was gathered from 41 vena cava occlusion manoeuvres performed experimentally at a variety of PEEPs across 6 porcine specimens, and ESPVR determined for each pig. An exponential model of ESPVR was found to provide a higher correlation coefficient than a linear model in 6 out of 7 cases, and a lower Akaike Information Criterion (AIC) value in all cases. Further, the exponential ESPVR provided positive V0 values in a physiological range in 6 out of 7 cases analysed, while the linear ESPVR produced positive V0 values in only 3 out of 7 cases, suggesting linear extrapolation of ESPVR to determine V0 may be flawed.
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Hutchison J, Rea P. A comparative study of the morphology of mammalian chordae tendineae of the mitral and tricuspid valves. Vet Rec Open 2015; 2:e000150. [PMID: 26644912 PMCID: PMC4667175 DOI: 10.1136/vetreco-2015-000150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 10/19/2015] [Accepted: 10/22/2015] [Indexed: 11/16/2022] Open
Abstract
It is assumed that the human heart is almost identical to domestic mammalian species, but with limited literature to support this. One such area that has been underinvestigated is that of the subvalvular apparatus level. The authors set out to examine the morphology of the subvalvular apparatus of the mammalian atrioventricular valves through gross dissection and microscopic analysis in a small-scale pilot study. The authors examined the chordae tendineae of the mitral and tricuspid valves in sheep, pig and bovine hearts, comparing the numbers of each of these structures within and between species. It was found that the number of chordae was up to twice as many for the tricuspid valve compared with the mitral valve. The counts for the chordae on the three valve leaflets of the tricuspid valve, as well as the two mitral valve leaflets, were almost identical between species. However, the chordae attaching onto the posterior papillary muscle were almost double compared with the septal and anterior papillary muscles. Histological analysis demonstrated an abrupt transitional zone. In conclusion, the authors have shown that there is no gross morphological difference between, or within, these species at the subvalvular apparatus level.
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Affiliation(s)
- Jennifer Hutchison
- Laboratory of Human Anatomy , School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow , UK
| | - Paul Rea
- Laboratory of Human Anatomy , School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow , UK
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Gonzalez-Bulnes A, Torres-Rovira L, Astiz S, Ovilo C, Sanchez-Sanchez R, Gomez-Fidalgo E, Perez-Solana M, Martin-Lluch M, Garcia-Contreras C, Vazquez-Gomez M. Fetal Sex Modulates Developmental Response to Maternal Malnutrition. PLoS One 2015; 10:e0142158. [PMID: 26544862 PMCID: PMC4636307 DOI: 10.1371/journal.pone.0142158] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 10/19/2015] [Indexed: 12/24/2022] Open
Abstract
The incidence of obesity and metabolic diseases is dramatically high in rapidly developing countries. Causes have been related to intrinsic ethnic features with development of a thrifty genotype for adapting to food scarcity, prenatal programming by undernutrition, and postnatal exposure to obesogenic lifestyle. Observational studies in humans and experimental studies in animal models evidence that the adaptive responses of the offspring may be modulated by their sex. In the contemporary context of world globalization, the new question arising is the existence and extent of sex-related differences in developmental and metabolic traits in case of mixed-race. Hence, in the current study, using a swine model, we compared male and female fetuses that were crossbred from mothers with thrifty genotype and fathers without thrifty genotype. Female conceptuses evidence stronger protective strategies for their adequate growth and postnatal survival. In brief, both male and female fetuses developed a brain-sparing effect but female fetuses were still able to maintain the development of other viscerae than the brain (mainly liver, intestine and kidneys) at the expense of carcass development. Furthermore, these morphometric differences were reinforced by differences in nutrient availability (glucose and cholesterol) favoring female fetuses with severe developmental predicament. These findings set the basis for further studies aiming to increase the knowledge on the interaction between genetic and environmental factors in the determination of adult phenotype
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Radford GE, Taylor MC, Kieser JA, Waddell JN, Walsh KAJ, Schofield JC, Das R, Chakravorty E. Simulating backspatter of blood from cranial gunshot wounds using pig models. Int J Legal Med 2015; 130:985-994. [PMID: 26156450 DOI: 10.1007/s00414-015-1219-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 06/22/2015] [Indexed: 11/29/2022]
Abstract
Few studies have examined the biomechanical basis for backspatter from cranial gunshot wounds. Backspatter is material which travels against the direction of fire following ejection from a gunshot entrance wound. Our paper focuses on the use of animals for reconstructing this phenomenon. Five live pigs and several slaughtered pigs were shot using either 9 × 19 mm, 115 grain, full metal jacketed ammunition or .22 long rifle, 40 grain, lead, round-nose ammunition. A high-speed camera was used to record the entrance wound formation and backspatter. A small amount of backspattered material was produced with all targets, and blood backspatter was seen in a few cases. However, we conclude that our model provides an understanding of the phenomenon of backspatter and the physical mechanisms associated with it. The various components of the mechanism of backspatter formation are complex and overlap. The principle mechanism observed in pig cranial gunshots was the high-speed impact response of the skin overlying the skull bone. This study has also produced evidence supporting the view that backspatter can result from the splashing of superficial blood if it is already present on the skin. Subcutaneous gas effects have been demonstrated for backspatter from contact shots. There has been no clear evidence of the role of the collapse of a temporary cavity within the brain.
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Affiliation(s)
- G E Radford
- University of Otago, PO Box 54, Dunedin, 9054, New Zealand
| | - M C Taylor
- Institute of Environmental Science and Research (ESR), Christchurch Science Centre, 27 Creyke Rd, Christchurch, 8041, New Zealand.
| | - J A Kieser
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, PO Box 647, Dunedin, 9054, New Zealand
| | - J N Waddell
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, PO Box 647, Dunedin, 9054, New Zealand
| | - K A J Walsh
- Institute of Environmental Science and Research (ESR), Mount Albert Science Centre, 120 Mount Albert Road, Auckland, 1142, New Zealand
| | - J C Schofield
- University of Otago, PO Box 54, Dunedin, 9054, New Zealand
| | - R Das
- Department of Mechanical Engineering, University of Auckland, Auckland, 1010, New Zealand
| | - E Chakravorty
- Department of Mechanical Engineering, University of Auckland, Auckland, 1010, New Zealand
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Porcine models of digestive disease: the future of large animal translational research. Transl Res 2015; 166:12-27. [PMID: 25655839 PMCID: PMC4458388 DOI: 10.1016/j.trsl.2015.01.004] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 01/03/2015] [Accepted: 01/07/2015] [Indexed: 12/14/2022]
Abstract
There is increasing interest in nonrodent translational models for the study of human disease. The pig, in particular, serves as a useful animal model for the study of pathophysiological conditions relevant to the human intestine. This review assesses currently used porcine models of gastrointestinal physiology and disease and provides a rationale for the use of these models for future translational studies. The pig has proven its utility for the study of fundamental disease conditions such as ischemia-reperfusion injury, stress-induced intestinal dysfunction, and short bowel syndrome. Pigs have also shown great promise for the study of intestinal barrier function, surgical tissue manipulation and intervention, as well as biomaterial implantation and tissue transplantation. Advantages of pig models highlighted by these studies include the physiological similarity to human intestine and mechanisms of human disease. Emerging future directions for porcine models of human disease include the fields of transgenics and stem cell biology, with exciting implications for regenerative medicine.
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Ardila DC, Tamimi E, Danford FL, Haskett DG, Kellar RS, Doetschman T, Vande Geest JP. TGFβ2 differentially modulates smooth muscle cell proliferation and migration in electrospun gelatin-fibrinogen constructs. Biomaterials 2015; 37:164-73. [PMID: 25453947 PMCID: PMC4312204 DOI: 10.1016/j.biomaterials.2014.10.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 10/02/2014] [Indexed: 01/14/2023]
Abstract
A main goal of tissue engineering is the development of scaffolds that replace, restore and improve injured tissue. These scaffolds have to mimic natural tissue, constituted by an extracellular matrix (ECM) support, cells attached to the ECM, and signaling molecules such as growth factors that regulate cell function. In this study we created electrospun flat sheet scaffolds using different compositions of gelatin and fibrinogen. Smooth muscle cells (SMCs) were seeded on the scaffolds, and proliferation and infiltration were evaluated. Additionally, different concentrations of Transforming Growth Factor-beta2 (TGFβ2) were added to the medium with the aim of elucidating its effect on cell proliferation, migration and collagen production. Our results demonstrated that a scaffold with a composition of 80% gelatin-20% fibrinogen is suitable for tissue engineering applications since it promotes cell growth and migration. The addition of TGFβ2 at low concentrations (≤ 1 ng/ml) to the culture medium resulted in an increase in SMC proliferation and scaffold infiltration, and in the reduction of collagen production. In contrast, TGFβ2 at concentrations >1 ng/ml inhibited cell proliferation and migration while stimulating collagen production. According to our results TGFβ2 concentration has a differential effect on SMC function and thus can be used as a biochemical modulator that can be beneficial for tissue engineering applications.
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Affiliation(s)
- Diana C Ardila
- Graduate Interdisciplinary Program of Biomedical Engineering, The University of Arizona, Tucson, AZ 85721, USA
| | - Ehab Tamimi
- Graduate Interdisciplinary Program of Biomedical Engineering, The University of Arizona, Tucson, AZ 85721, USA
| | - Forest L Danford
- Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, AZ 85721, USA
| | - Darren G Haskett
- Graduate Interdisciplinary Program of Biomedical Engineering, The University of Arizona, Tucson, AZ 85721, USA
| | - Robert S Kellar
- Center for Bioengineering Innovation, Northern Arizona University, Flagstaff, AZ 86011, USA; Department of Mechanical Engineering, Northern Arizona University, Flagstaff, AZ 86011, USA; Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA
| | - Tom Doetschman
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ 85721, USA; Sarver Heart Center, The University of Arizona, Tucson, AZ 85724, USA; BIO5 Institute for Biocollaborative Research, The University of Arizona, Tucson, AZ 85721, USA
| | - Jonathan P Vande Geest
- Graduate Interdisciplinary Program of Biomedical Engineering, The University of Arizona, Tucson, AZ 85721, USA; Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, AZ 85721, USA; BIO5 Institute for Biocollaborative Research, The University of Arizona, Tucson, AZ 85721, USA; Department of Biomedical Engineering, The University of Arizona, Tucson, AZ 85721, USA.
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Gonzalez-Bulnes A, Astiz S, Ovilo C, Lopez-Bote CJ, Sanchez-Sanchez R, Perez-Solana ML, Torres-Rovira L, Ayuso M, Gonzalez J. Early-postnatal changes in adiposity and lipids profile by transgenerational developmental programming in swine with obesity/leptin resistance. J Endocrinol 2014; 223:M17-29. [PMID: 25107535 DOI: 10.1530/joe-14-0217] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Maternal malnutrition during pregnancy, both deficiency and excess, induces changes in the intrauterine environment and the metabolic status of the offspring, playing a key role in the growth, status of fitness/obesity and appearance of metabolic disorders during postnatal life. There is increasing evidence that these effects may not be only limited to the first generation of descendants, the offspring directly exposed to metabolic challenges, but to subsequent generations. This study evaluated, in a swine model of obesity/leptin resistance, the existence and extent of transgenerational developmental programming effects. Pre- and postnatal development, adiposity and metabolic features were assessed in the second generation of piglets, descendant of sows exposed to either undernutrition or overnutrition during pregnancy. The results indicated that these piglets exhibited early-postnatal increases in adiposity and disturbances in lipid profiles compatible with the early prodrome of metabolic syndrome, with liver tissue also displaying evidence of paediatric liver disease. These features indicative of early-life metabolic disorders were more evident in the males that were descended from overfed grandmothers and during the transition from milk to solid feeding. Thus, this study provides evidence supporting transgenerational developmental programming and supports the necessity for the development of strategies for avoiding the current epidemics of childhood overweight and obesity.
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Affiliation(s)
- Antonio Gonzalez-Bulnes
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Susana Astiz
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Cristina Ovilo
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Clemente J Lopez-Bote
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Raul Sanchez-Sanchez
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Maria L Perez-Solana
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Laura Torres-Rovira
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Miriam Ayuso
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
| | - Jorge Gonzalez
- Departamento de Reproducción AnimalINIA, Avenida Puerta de Hierro s/n, Madrid 28040, SpainDepartamento de Mejora Genética AnimalINIA, Ctra. La Coruña km 7.5, Madrid 28040, SpainFacultad de VeterinariaUniversidad Complutense de Madrid, Madrid 28040, SpainMicros VeterinariaCampus de Vegazana, Leon 24007, Spain
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Mikulewicz M, Wołowiec P, Janeczek M, Gedrange T, Chojnacka K. The release of metal ions from orthodontic appliances animal tests. Angle Orthod 2014; 84:673-9. [PMID: 24417497 DOI: 10.2319/090213-641.1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE To investigate the release of metal ions from an orthodontic appliance in tests on animals (pigs). MATERIALS AND METHODS An animal test was conducted on 24 pigs divided equally into an experimental and a control group. In total, 12 sets of experimental orthodontic plates were surgically inserted into pig snouts in the experimental group for 6 months. Noninvasive matrices (hair [0, 3, and 6 months]) and invasive matrices (kidneys, liver, lungs, aorta, and oral mucosa) were collected for multi-elemental analysis (inductively coupled plasma optical emission spectrometry) from the experimental and control groups. RESULTS The greatest differences in the content of toxic metals were found in the aorta (Ni level was 4.8 times higher in experimental than in the control group), in the cheek (Ni 3.5 times higher), and in the hair sampled after 3 months (Cr 3.4 times higher). CONCLUSIONS The obtained data indicate that the products of corrosion have passed into selected tissues of pigs; however, the doses of toxic metal ions released from the appliance did not reach toxic levels.
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Affiliation(s)
- Marcin Mikulewicz
- a Assistant Professor, Department of Dentofacial Orthopeadics and Orthodontics, Medical University of Wrocław, Wrocław, Poland
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Barbero A, Astiz S, Lopez-Bote CJ, Perez-Solana ML, Ayuso M, Garcia-Real I, Gonzalez-Bulnes A. Maternal malnutrition and offspring sex determine juvenile obesity and metabolic disorders in a swine model of leptin resistance. PLoS One 2013; 8:e78424. [PMID: 24205230 PMCID: PMC3813450 DOI: 10.1371/journal.pone.0078424] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 09/20/2013] [Indexed: 11/19/2022] Open
Abstract
The present study aimed to determine, in a swine model of leptin resistance, the effects of type and timing of maternal malnutrition on growth patterns, adiposity and metabolic features of the progeny when exposed to an obesogenic diet during their juvenile development and possible concomitant effects of the offspring sex. Thus, four groups were considered. A CONTROL group involved pigs born from sows fed with a diet fulfilling their daily maintenance requirements for pregnancy. The treated groups involved the progeny of females fed with the same diet but fulfilling either 160% or 50% of pregnancy requirements during the entire gestation (OVERFED and UNDERFED, respectively) or 100% of requirements until Day 35 of pregnancy and 50% of such amount from Day 36 onwards (LATE-UNDERFED). OVERFED and UNDERFED offspring were more prone to higher corpulence and fat deposition from early postnatal stages, during breast-feeding; adiposity increased significantly when exposed to obesogenic diets, especially in females. The effects of sex were even more remarkable in LATE-UNDERFED offspring, which had similar corpulence to CONTROL piglets; however, females showed a clear predisposition to obesity. Furthermore, the three groups of pigs with maternal malnutrition showed evidences of metabolic syndrome and, in the case of individuals born from OVERFED sows, even of insulin resistance and the prodrome of type-2 diabetes. These findings support the main role of early nutritional programming in the current rise of obesity and associated diseases in ethnics with leptin resistance.
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Ye J, He J, Li Q, Feng Y, Bai X, Chen X, Zhao Y, Hu X, Yu Z, Li N. Generation of c-Myc transgenic pigs for autosomal dominant polycystic kidney disease. Transgenic Res 2013; 22:1231-9. [PMID: 23543409 DOI: 10.1007/s11248-013-9707-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 03/22/2013] [Indexed: 01/28/2023]
Abstract
After several decades of research, autosomal dominant polycystic kidney disease (ADPKD) is still incurable and imposes enormous physical, psychological, and economic burdens on patients and their families. Murine models of ADPKD represent invaluable tools for studying this disease. These murine forms of ADPKD can arise spontaneously, or they can be induced via chemical or genetic manipulations. Although these models have improved our understanding of the etiology and pathogenesis of ADPKD, they have not led to effective treatment strategies. The mini-pig represents an effective biomedical model for studying human diseases, as the pig's human-like physiological processes help to understand disease mechanisms and to develop novel therapies. Here, we tried to generate a transgenic model of ADPKD in pigs by overexpressing c-Myc in kidney tissue. Western-blot analysis showed that c-Myc was overexpressed in the kidney, brain, heart, and liver of transgenic pigs. Immunohistochemical staining of kidney tissue showed that exogenous c-Myc predominantly localized to renal tubules. Slightly elevated blood urea nitrogen levels were observed in transgenic pigs 1 month after birth, but no obvious abnormalities were detected after that time. In the future, we plan to subject this model to renal injury in an effort to promote ADPKD progression.
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Affiliation(s)
- Jianhua Ye
- State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, 100193, China,
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Isolation, characterization and differentiation potential of cardiac progenitor cells in adult pigs. Stem Cell Rev Rep 2012; 8:706-19. [PMID: 22228441 DOI: 10.1007/s12015-011-9339-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Characterization of Porcine Ventral Mesencephalic Precursor Cells following Long-Term Propagation in 3D Culture. Stem Cells Int 2012; 2012:761843. [PMID: 23258982 PMCID: PMC3508616 DOI: 10.1155/2012/761843] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 09/04/2012] [Indexed: 01/08/2023] Open
Abstract
The potential use of predifferentiated neural precursor cells for treatment of a neurological disorder like Parkinson's disease combines stem cell research with previous experimental and clinical transplantation of developing dopaminergic neurons. One current obstacle is, however, the lack of ability to generate dopaminergic neurons after long-term in vitro propagation of the cells. The domestic pig is considered a useful nonprimate large animal model in neuroscience, because of a better resemblance of the larger gyrencephalic pig brain to the human brain than the commonly used brains of smaller rodents. In the present study, porcine embryonic (28–30 days), ventral mesencephalic precursor cells were isolated and propagated as free-floating neural tissue spheres in medium containing epidermal growth factor and fibroblast growth factor 2. For passaging, the tissue spheres were cut into quarters, avoiding mechanical or enzymatic dissociation in order to minimize cellular trauma and preserve intercellular contacts. Spheres were propagated for up to 237 days with analysis of cellular content and differentiation at various time points. Our study provides the first demonstration that porcine ventral mesencephalic precursor cells can be long-term propagated as neural tissue spheres, thereby providing an experimental 3D in vitro model for studies of neural precursor cells, their niche, and differentiation capacity.
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Walters EM, Wolf E, Whyte JJ, Mao J, Renner S, Nagashima H, Kobayashi E, Zhao J, Wells KD, Critser JK, Riley LK, Prather RS. Completion of the swine genome will simplify the production of swine as a large animal biomedical model. BMC Med Genomics 2012; 5:55. [PMID: 23151353 PMCID: PMC3499190 DOI: 10.1186/1755-8794-5-55] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Accepted: 10/28/2011] [Indexed: 12/25/2022] Open
Abstract
Background Anatomic and physiological similarities to the human make swine an excellent large animal model for human health and disease. Methods Cloning from a modified somatic cell, which can be determined in cells prior to making the animal, is the only method available for the production of targeted modifications in swine. Results Since some strains of swine are similar in size to humans, technologies that have been developed for swine can be readily adapted to humans and vice versa. Here the importance of swine as a biomedical model, current technologies to produce genetically enhanced swine, current biomedical models, and how the completion of the swine genome will promote swine as a biomedical model are discussed. Conclusions The completion of the swine genome will enhance the continued use and development of swine as models of human health, syndromes and conditions.
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Affiliation(s)
- Eric M Walters
- National Swine Resource and Research Center, University of Missouri, Columbia, MO 65211, USA.
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Ganderup NC, Harvey W, Mortensen JT, Harrouk W. The minipig as nonrodent species in toxicology--where are we now? Int J Toxicol 2012; 31:507-28. [PMID: 23134714 DOI: 10.1177/1091581812462039] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Over the past 3 decades minipigs have moved from being an obscure alternative to dogs and nonhuman primates to being a standard animal model in regulatory toxicity studies. This article covers the use of minipigs as a model in the context of nonclinical drug safety and provides an overview of the minipig's developmental history and relates minipigs to other animal species commonly used in toxicology; and the minipig's translational power is supported by 43 case studies of marketed drug products covered. Special focus is given to criteria for selecting minipigs in nonclinical programs supporting the development of new medicines; the use of swine in the assessment of food additives, agrochemicals, and pesticides; as well as a regulatory perspective on the use of minipigs in Food and Drug Administration (FDA)-regulated products. This article presents the main points conveyed at a symposium held at the 2010 American College of Toxicology meeting in Baltimore, Maryland.
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Thomsen M, Poulsen M, Bech M, Velroyen A, Herzen J, Beckmann F, Feidenhans'l R, Pfeiffer F. Visualization of subcutaneous insulin injections by x-ray computed tomography. Phys Med Biol 2012; 57:7191-203. [PMID: 23060123 DOI: 10.1088/0031-9155/57/21/7191] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We report how the three-dimensional structure of subcutaneous injections of soluble insulin can be visualized by x-ray computed tomography using an iodine based contrast agent. The injections investigated are performed ex vivo in porcine adipose tissue. Full tomography scans carried out at a laboratory x-ray source with a total acquisition time of about 1 min yield CT-images with an effective pixel size of 109 × 109 μm². The depots are segmented using a modified Chan-Vese algorithm and we are able to observe differences in the shape of the injection depot and the position of the depot in the skin among equally performed injections. To overcome the beam hardening artefacts, which affect the quantitative prediction of the volume injected, we additionally present results concerning the visualization of two injections using synchrotron radiation. The spatial concentration distribution of iodine is calculated to show the dilution of the insulin drug inside the depot. Characterisation of the shape of the depot and the spatial concentration profile of the injected fluid is important knowledge when improving the clinical formulation of an insulin drug, the performance of injection devices and when predicting the effect of the drug through biomedical simulations.
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Affiliation(s)
- M Thomsen
- Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark.
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Gonzalez-Bulnes A, Ovilo C, Lopez-Bote CJ, Astiz S, Ayuso M, Perez-Solana ML, Sanchez-Sanchez R, Torres-Rovira L. Gender-specific early postnatal catch-up growth after intrauterine growth retardation by food restriction in swine with obesity/leptin resistance. Reproduction 2012; 144:269-78. [DOI: 10.1530/rep-12-0105] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The effects of undernutrition during pregnancy on prenatal and postnatal development of the offspring were evaluated in sows with obesity/leptin resistance. Females were fed, from day 35 of pregnancy onwards, a diet fulfilling either 100% (group control,n=10) or 50% of the nutritional requirements (group underfed,n=10). In the control group, maternal body weight increased during pregnancy (P<0.05) while it decreased or remained steady in the underfed group. At days 75 and 100 of gestation, plasma triglycerides were lower but urea levels were higher in restricted than in control sows (P<0.05 for both). Assessment of the offspring indicated that the trunk diameter was always smaller in the restricted group (P<0.01 at day 50,P<0.005 at days 75 and 100 andP<0.0001 at birth) while head measurements were similar through pregnancy, although smaller in the restricted than in the control group at birth (P<0.05). Newborns from restricted sows were also lighter than offspring from control females (P<0.01) and had higher incidence of growth retardation (P<0.01). Afterwards, during lactation, early postnatal growth in restricted piglets was modulated by gender. At weaning, males from restricted sows were still lighter than their control counterparts (P<0.05), while females from control and underfed sows were similar. Thus, the current study indicates a gender-related differential effect in the growth patterns of the piglets, with females from restricted sows evidencing catch-up growth to neutralise prenatal retardation and reaching similar development than control counterparts.
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Torres-Rovira L, Astiz S, Caro A, Lopez-Bote C, Ovilo C, Pallares P, Perez-Solana ML, Sanchez-Sanchez R, Gonzalez-Bulnes A. Diet-induced swine model with obesity/leptin resistance for the study of metabolic syndrome and type 2 diabetes. ScientificWorldJournal 2012; 2012:510149. [PMID: 22629144 PMCID: PMC3354447 DOI: 10.1100/2012/510149] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2011] [Accepted: 12/22/2011] [Indexed: 12/13/2022] Open
Abstract
The objective of the present study was to determine the suitability of a swine breed with leptin resistance and predisposition to obesity (the Iberian pig) as model for studies on metabolic syndrome and type 2 diabetes. Thus, six Iberian sows had ad libitum access to food enriched with saturated fat (SFAD group; food consumption was estimated to be 4.5 kg/animal/day) whilst four females acted as controls and were fed with 2 kg/animal/day of a commercial maintenance diet. After three months of differential feeding, SFAD animals developed central obesity, dyslipidemia, insulin resistance and impaired glucose tolerance, and elevated blood pressure; the five parameters associated with the metabolic syndrome. Thus, the current study characterizes the Iberian pig as a robust, amenable, and reliable translational model for studies on nutrition-associated diseases.
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Affiliation(s)
- L Torres-Rovira
- Departamento de Reproducción Animal, INIA, 28040 Madrid, Spain
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Wei J, Ouyang H, Wang Y, Pang D, Cong NX, Wang T, Leng B, Li D, Li X, Wu R, Ding Y, Gao F, Deng Y, Liu B, Li Z, Lai L, Feng H, Liu G, Deng X. Characterization of a hypertriglyceridemic transgenic miniature pig model expressing human apolipoprotein CIII. FEBS J 2011; 279:91-9. [PMID: 22023023 DOI: 10.1111/j.1742-4658.2011.08401.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Hypertriglyceridemia has recently been considered to be an independent risk factor for coronary heart disease, in which apolipoprotein (Apo)CIII is one of the major contributory factors, as it is strongly correlated with plasma triglyceride levels. Although ApoCIII transgenic mice have been generated as an animal model for the study of hypertriglyceridemia, the features of lipoprotein metabolism in mice differ greatly from those in humans. Because of the great similarity between pigs and humans with respect to lipid metabolism and cardiovascular physiology, we generated transgenic miniature pigs expressing human ApoCIII by the transfection of somatic cells combined with nuclear transfer. The expression of human ApoCIII was detected in the liver and intestine of the transgenic pigs. As compared with nontransgenic controls, transgenic pigs showed significantly increased plasma triglyceride levels (83 ± 36 versus 38 ± 4 mg·dL(-1), P < 0.01) when fed a chow diet. Plasma lipoprotein profiling by FPLC in transgenic animals showed a higher peak in large-particle fractions corresponding to very low-density lipoprotein/chylomicrons when triglyceride content in the fractions was assayed. There was not much difference in cholesterol content in FPLC fractions, although a large low-density lipoprotein peak was identified in both nontransgenic and transgenic animals, resembling that found in humans. Further analysis revealed markedly delayed clearance of plasma triglyceride, accompanied by significantly reduced lipoprotein lipase activity in post-heparin plasma, in transgenic pigs as compared with nontransgenic controls. In summary, we have successfully generated a novel hypertriglyceridemic ApoCIII transgenic miniature pig model that could be of great value for studies on hyperlipidemia in relation to atherosclerotic disorders.
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Affiliation(s)
- Jingyuan Wei
- Laboratory Animal Center, Jilin University, Changchun, China
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