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Hargrave B.,Old Dominion University | Strange R.,Naval Medical Center Portsmouth | Navare S.,Naval Medical Center Portsmouth | Stratton M.,Naval Medical Center Portsmouth | And 6 more authors.
PLoS ONE | Year: 2014

Myocardial ischemia can damage heart muscle and reduce the heart's pumping efficiency. This study used an ischemic swine heart model to investigate the potential for gene electro transfer of a plasmid encoding vascular endothelial growth factor for improving perfusion and, thus, for reducing cardiomyopathy following acute coronary syndrome. Plasmid expression was significantly greater in gene electro transfer treated tissue compared to injection of plasmid encoding vascular endothelial growth factor alone. Higher gene expression was also seen in ischemic versus non-ischemic groups with parameters 20 Volts (p<0.03), 40 Volts (p<0.05), and 90 Volts (p<0.05), but not with 60 Volts (p<0.09) while maintaining a pulse width of 20 milliseconds. The group with gene electro transfer of plasmid encoding vascular endothelial growth factor had increased perfusion in the area at risk compared to control groups. Troponin and creatine kinase increased across all groups, suggesting equivalent ischemia in all groups prior to treatment. Echocardiography was used to assess ejection fraction, cardiac output, stroke volume, left ventricular end diastolic volume, and left ventricular end systolic volume. No statistically significant differences in these parameters were detected during a 2-week time period. However, directional trends of these variables were interesting and offer valuable information about the feasibility of gene electro transfer of vascular endothelial growth factor in the ischemic heart. The results demonstrate that gene electro transfer can be applied safely and can increase perfusion in an ischemic area. Additional study is needed to evaluate potential efficacy.


Mattison J.A.,U.S. National Institute on Aging | Roth G.S.,GeroScience | Mark Beasley T.,University of Alabama at Birmingham | Tilmont E.M.,U.S. National Institute on Aging | And 12 more authors.
Nature | Year: 2012

Calorie restriction (CR), a reduction of 10-40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7-14-years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate. © 2012 Macmillan Publishers Limited. All rights reserved.


Bulysheva A.A.,Old Dominion University | Hargrave B.,Old Dominion University | Burcus N.,Old Dominion University | Lundberg C.G.,Old Dominion University | And 2 more authors.
IFMBE Proceedings | Year: 2016

Gene electro transfer to the left ventricular myocardium is a promising technique for delivery of therapeutic genes for treatment of ischemia, myocardial infarction and heart failure directly to the effected myocardium. There are multiple variables to consider for efficient gene delivery and gene expression modulation, including electro transfer parameters, timing and duration of pulses relative to the electrocardiogram and ischemic state. Here we report establishing a small animal model and a large animal model for gene delivery to non-ischemic and ischemic left ventricular myocardium. Gene expression was evaluated histologically for location of expression within the myocardium as well as quantitatively via ELISA. We developed electro transfer electrodes and protocols that are safe and result robust gene expression. These animal models allow for evaluation of therapeutic potential of particular gene delivery as well as translation to clinical settings. © Springer Science+Business Media Singapore 2016.


PubMed | SoBran Inc. and Old Dominion University
Type: Journal Article | Journal: Gene therapy | Year: 2016

This study aimed to assess safety and therapeutic potential of gene electrotransfer (GET) as a method for delivery of plasmid encoding vascular endothelial growth factor A (VEGF-A) to ischemic myocardium in a porcine model. Myocardial ischemia was induced by surgically occluding the left anterior descending coronary artery in swine. GET following plasmid encoding VEGF-A injection was performed at four sites in the ischemic region. Control groups either received injections of the plasmid without electrotransfer or injections of the saline vehicle. Animals were monitored for 7 weeks and the hearts were evaluated for angiogenesis, myocardial infarct size and left ventricular contractility. Arteriograms suggest growth of new arteries as early as 2 weeks after treatment in electrotransfer animals. There is a significant reduction of infarct area and left ventricular contractility is improved in GET-treated group compared with controls. There was no significant difference in mortality of animals treated with GET of plasmid encoding VEGF-A from the control groups. Gene delivery of plasmid encoding VEGF-A to ischemic myocardium in a porcine model can be accomplished safely with potential for myocardial repair and regeneration.


Gozalo A.S.,National Institute of Allergy and Infectious Diseases | Gozalo A.S.,SoBran Inc. | Zerfas P.M.,U.S. National Institutes of Health | Starost M.F.,U.S. National Institutes of Health | And 2 more authors.
Journal of Medical Primatology | Year: 2010

Background An adult male owl monkey (Aotus nancymae) underwent a splenectomy. When the spleen was removed, a small, nodular mass slightly bulging over the splenic surface was noted.Methods The mass was examined by light and transmission electron microscopy and by immunohistochemistry.Results On light microscopy, the mass was well-circumscribed, non-encapsulated, and composed of haphazardly arranged smooth muscle bundles admixed with numerous small capillary-like structures containing blood. Immunohistochemical (IHC) staining revealed the tumor was strongly positive for smooth muscle actin yielding vascular smooth muscle bundles, and for Factor VIII, staining endothelial cells within the smooth muscle bundles. Transmission electron microscopy (TEM) showed a large portion of the cells to be atypical appearing smooth muscle and a few cells had structures resembling Weibel-Palade bodies indicating endothelial cells.Conclusions Based on cell morphology, by light and TEM, and IHC a final diagnosis of splenic angioleiomyoma was made. This is, to our knowledge, the first report of an angioleiomyoma in a non-human primate. © 2010.


Vaughan K.L.,U.S. National Institute on Aging | Vaughan K.L.,SoBran Inc. | Szarowicz M.D.,U.S. National Institute on Aging | Szarowicz M.D.,SoBran Inc. | And 2 more authors.
Journal of Medical Primatology | Year: 2014

Background: Drugs commonly used to sedate non-human primates for physiological sample collection can affect the metabolic system and alter rates of glucose metabolism. This study was designed to compare the physiological and metabolic effects of ketamine/diazepam, telazol, and ketamine/dexmedetomidine. Methods: Seven female rhesus monkeys underwent intravenous glucose tolerance testing under each of three anesthesia conditions. Blood glucose, insulin, physiological parameters, and sedation characteristics were measured and recorded. Results: Glucose and insulin values were both significantly impacted by ketamine/dexmedetomidine sedation while remaining consistent during ketamine and telazol sedation. Heart rate was also significantly lowered during ketamine/dexmedetomidine anesthesia. Though, ketamine/dexmedetomidine resulted in a longer time between induction of anesthesia and need for a supplemental dose of anesthesia drug. Conclusions: Telazol and ketamine have minimal cardiorespiratory and metabolic effects compared to ketamine/dexmedetomidine. Although practicably interchangeable, telazol appears to be the most efficient for intravenous glucose tolerance testings with non-human primates. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.


Ortega-Molina A.,Tumor Suppression Group | Lopez-Guadamillas E.,Tumor Suppression Group | Mattison J.A.,U.S. National Institute on Aging | Mitchell S.J.,U.S. National Institute on Aging | And 14 more authors.
Cell Metabolism | Year: 2015

Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans. © 2015 Elsevier Inc.


Paukner A.,U.S. National Institutes of Health | Huntsberry M.E.,U.S. National Institutes of Health | Huntsberry M.E.,SoBran Inc. | Suomi S.J.,U.S. National Institutes of Health
Developmental Psychobiology | Year: 2010

Recent studies have revealed that human infants process female faces differently from male faces. To test whether a similar preference for female faces exists in other primates, we presented nursery-reared infant rhesus macaques with photographs of macaque faces and human faces. At <1 month old, infant macaques preferentially oriented towards female macaque faces when faces were presented upright. No preference for female human faces was found. At 9 months old, infants failed to show a visual preference for female macaque faces or female human faces, although they showed significantly more lipsmacking responses at female human faces. Compared to human infants, macaques appear to have stronger predis-positions early in life but this preference may nonetheless be amendable to experience. Understanding how innate predispositions and the social rearing environment shape infants' understanding of faces remain important issues to be explored in order to understand facial processing abilities in humans and other primates. © 2009 Wiley Periodicals, Inc.

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