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Sample records for non-human primate model

  1. Immunology studies in non-human primate models of tuberculosis.

    PubMed

    Flynn, JoAnne L; Gideon, Hannah P; Mattila, Joshua T; Lin, Philana Ling

    2015-03-01

    Non-human primates, primarily macaques, have been used to study tuberculosis for decades. However, in the last 15 years, this model has been refined substantially to allow careful investigations of the immune response and host-pathogen interactions in Mycobacterium tuberculosis infection. Low-dose challenge with fully virulent strains in cynomolgus macaques result in the full clinical spectrum seen in humans, including latent and active infection. Reagents from humans are usually cross-reactive with macaques, further facilitating the use of this model system to study tuberculosis. Finally, macaques develop the spectrum of granuloma types seen in humans, providing a unique opportunity to investigate bacterial and host factors at the local (lung and lymph node) level. Here, we review the past decade of immunology and pathology studies in macaque models of tuberculosis.

  2. A Non-Human Primate Model of Severe Pneumococcal Pneumonia

    PubMed Central

    Reyes, Luis F.; Restrepo, Marcos I.; Hinojosa, Cecilia A.; Soni, Nilam J.; Shenoy, Anukul T.; Gilley, Ryan P.; Gonzalez-Juarbe, Norberto; Noda, Julio R.; Winter, Vicki T.; de la Garza, Melissa A.; Shade, Robert E.; Coalson, Jacqueline J.; Giavedoni, Luis D.; Anzueto, Antonio; Orihuela, Carlos J.

    2016-01-01

    Rationale Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and infectious death in adults worldwide. A non-human primate model is needed to study the molecular mechanisms that underlie the development of severe pneumonia, identify diagnostic tools, explore potential therapeutic targets, and test clinical interventions during pneumococcal pneumonia. Objective To develop a non-human primate model of pneumococcal pneumonia. Methods Seven adult baboons (Papio cynocephalus) were surgically tethered to a continuous monitoring system that recorded heart rate, temperature, and electrocardiography. Animals were inoculated with 109 colony-forming units of S. pneumoniae using bronchoscopy. Three baboons were rescued with intravenous ampicillin therapy. Pneumonia was diagnosed using lung ultrasonography and ex vivo confirmation by histopathology and immunodetection of pneumococcal capsule. Organ failure, using serum biomarkers and quantification of bacteremia, was assessed daily. Results Challenged animals developed signs and symptoms of pneumonia 4 days after infection. Infection was characterized by the presence of cough, tachypnea, dyspnea, tachycardia and fever. All animals developed leukocytosis and bacteremia 24 hours after infection. A severe inflammatory reaction was detected by elevation of serum cytokines, including Interleukin (IL)1Ra, IL-6, and IL-8, after infection. Lung ultrasonography precisely detected the lobes with pneumonia that were later confirmed by pathological analysis. Lung pathology positively correlated with disease severity. Antimicrobial therapy rapidly reversed symptomology and reduced serum cytokines. Conclusions We have developed a novel animal model for severe pneumococcal pneumonia that mimics the clinical presentation, inflammatory response, and infection kinetics seen in humans. This is a novel model to test vaccines and treatments, measure biomarkers to diagnose pneumonia, and predict outcomes. PMID:27855182

  3. Non-Human Primate Models for AIDS Vaccine Research

    PubMed Central

    Hu, Shiu-Lok

    2006-01-01

    Since the discovery of simian immunodeficiency viruses (SIV) causing AIDS-like diseases in Asian macaques, non-human primates (NHP) have played an important role in AIDS vaccine research. A multitude of vaccines and immunization approaches have been evaluated, including live attenuated viruses, DNA vaccines, viral and bacterial vectors, subunit proteins, and combinations thereof. Depending on the particular vaccine and model used, varying degrees of protection have been achieved, including prevention of infection, reduction of viral load, and amelioration of disease. In a few instances, potential safety concerns and vaccine-enhanced pathogenicity have also been noted. In the past decade, sophisticated methodologies have been developed to define the mechanisms of protective immunity. However, a clear road map for HIV vaccine development has yet to emerge. This is in part because of the intrinsic nature of the surrogate model and in part because of the improbability of any single model to fully capture the complex interactions of natural HIV infection in humans. The lack of standardization, the limited models available, and the incomplete understanding of the immunobiology of NHP contribute to the difficulty to extrapolate findings from such models to HIV vaccine development. Until efficacy data become available from studies of parallel vaccine concepts in humans and macaques, the predictive value of any NHP model remains unknown. Towards this end, greater appreciation of the utility and limitations of the NHP model and further developments to better mimic HIV infection in humans will likely help inform future AIDS vaccine efforts. PMID:15975024

  4. The Non-Human Primate Experimental Glaucoma Model

    PubMed Central

    Burgoyne, Claude F.

    2015-01-01

    The purpose of this report is to summarize the current strengths and weaknesses of the non-human primate (NHP) experimental glaucoma (EG) model through sections devoted to its history, methods, important findings, alternative optic neuropathy models and future directions. NHP EG has become well established for studying human glaucoma in part because the NHP optic nerve head (ONH) shares a close anatomic association with the human ONH and because it provides the only means of systematically studying the very earliest visual system responses to chronic IOP elevation, i.e. the conversion from ocular hypertension to glaucomatous damage. However, NHPs are impractical for studies that require large animal numbers, demonstrate spontaneous glaucoma only rarely, do not currently provide a model of the neuropathy at normal levels of IOP, and cannot easily be genetically manipulated, except through tissue-specific, viral vectors. The goal of this summary is to direct NHP EG and non-NHP EG investigators to the previous, current and future accomplishment of clinically relevant knowledge in this model. PMID:26070984

  5. Non-human Primate Models for Brain Disorders - Towards Genetic Manipulations via Innovative Technology.

    PubMed

    Qiu, Zilong; Li, Xiao

    2017-04-01

    Modeling brain disorders has always been one of the key tasks in neurobiological studies. A wide range of organisms including worms, fruit flies, zebrafish, and rodents have been used for modeling brain disorders. However, whether complicated neurological and psychiatric symptoms can be faithfully mimicked in animals is still debatable. In this review, we discuss key findings using non-human primates to address the neural mechanisms underlying stress and anxiety behaviors, as well as technical advances for establishing genetically-engineered non-human primate models of autism spectrum disorders and other disorders. Considering the close evolutionary connections and similarity of brain structures between non-human primates and humans, together with the rapid progress in genome-editing technology, non-human primates will be indispensable for pathophysiological studies and exploring potential therapeutic methods for treating brain disorders.

  6. Evaluation of Flow Biosensor Technology in a Chronically-Instrumented Non-Human Primate Model

    NASA Technical Reports Server (NTRS)

    Koenig, S. C.; Reister, C.; Schaub, J.; Muniz, G.; Ferguson, T.; Fanton, J. W.

    1995-01-01

    The Physiology Research Branch of Brooks AFB conducts both human and non-human primate experiments to determine the effects of microgravity and hypergravity on the cardiovascular system and to indentify the particular mechanisms that invoke these responses. Primary investigative research efforts in a non-human primate model require the calculation of total peripheral resistance (TPR), systemic arterial compliance (SAC), and pressure-volume loop characteristics. These calculations require beat-to-beat measurement of aortic flow. We have evaluated commercially available electromagnetic (EMF) and transit-time flow measurement techniques. In vivo and in vitro experiments demonstrated that the average error of these techniques is less than 25 percent for EMF and less than 10 percent for transit-time.

  7. Prospects for genetically modified non-human primate models, including the common marmoset.

    PubMed

    Sasaki, Erika

    2015-04-01

    Genetically modified mice have contributed much to studies in the life sciences. In some research fields, however, mouse models are insufficient for analyzing the molecular mechanisms of pathology or as disease models. Often, genetically modified non-human primate (NHP) models are desired, as they are more similar to human physiology, morphology, and anatomy. Recent progress in studies of the reproductive biology in NHPs has enabled the introduction of exogenous genes into NHP genomes or the alteration of endogenous NHP genes. This review summarizes recent progress in the production of genetically modified NHPs, including the common marmoset, and future perspectives for realizing genetically modified NHP models for use in life sciences research.

  8. Incorporating the gut microbiota into models of human and non-human primate ecology and evolution.

    PubMed

    Amato, Katherine R

    2016-01-01

    The mammalian gut is home to a diverse community of microbes. Advances in technology over the past two decades have allowed us to examine this community, the gut microbiota, in more detail, revealing a wide range of influences on host nutrition, health, and behavior. These host-gut microbe interactions appear to shape host plasticity and fitness in a variety of contexts, and therefore represent a key factor missing from existing models of human and non-human primate ecology and evolution. However, current studies of the gut microbiota tend to include limited contextual data or are clinical, making it difficult to directly test broad anthropological hypotheses. Here, I review what is known about the animal gut microbiota and provide examples of how gut microbiota research can be integrated into the study of human and non-human primate ecology and evolution with targeted data collection. Specifically, I examine how the gut microbiota may impact primate diet, energetics, disease resistance, and cognition. While gut microbiota research is proliferating rapidly, especially in the context of humans, there remain important gaps in our understanding of host-gut microbe interactions that will require an anthropological perspective to fill. Likewise, gut microbiota research will be an important tool for filling remaining gaps in anthropological research.

  9. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

    PubMed

    Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

    2014-11-18

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.

  10. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress

    PubMed Central

    ZHANG, Xiao-Liang; PANG, Wei; HU, Xin-Tian; LI, Jia-Li; YAO, Yong-Gang; ZHENG, Yong-Tang

    2014-01-01

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China’s growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China’s life sciences and pharmaceutical industry, and enhance China’s position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

  11. Why bother using non-human primate models of cognitive disorders in translational research?

    PubMed

    Camus, Sandrine; Ko, Wai Kin D; Pioli, Elsa; Bezard, Erwan

    2015-10-01

    Although everyone would agree that successful translation of therapeutic candidates for central nervous disorders should involve non-human primate (nhp) models of cognitive disorders, we are left with the paucity of publications reporting either the target validation or the actual preclinical testing in heuristic nhp models. In this review, we discuss the importance of nhps in translational research, highlighting the advances in technological/methodological approaches for 'bridging the gap' between preclinical and clinical experiments. In this process, we acknowledge that nhps remain a vital tool for the investigation of complex cognitive functions, given their resemblance to humans in aspects of behaviour, anatomy and physiology. The recent improvements made for a suitable nhp model in cognitive research, including new surrogates of disease and application of innovative methodological approaches, are continuous strides for reaching efficient translation for human benefit. This will ultimately aid the development of innovative treatments against the current and future threat of neurological and psychiatric disorders to the global population.

  12. A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta).

    PubMed

    Salegio, Ernesto A; Bresnahan, Jacqueline C; Sparrey, Carolyn J; Camisa, William; Fischer, Jason; Leasure, Jeremi; Buckley, Jennifer; Nout-Lomas, Yvette S; Rosenzweig, Ephron S; Moseanko, Rod; Strand, Sarah; Hawbecker, Stephanie; Lemoy, Marie-Josee; Haefeli, Jenny; Ma, Xiaokui; Nielson, Jessica L; Edgerton, V R; Ferguson, Adam R; Tuszynski, Mark H; Beattie, Michael S

    2016-03-01

    The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies.

  13. A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta)

    PubMed Central

    Salegio, Ernesto A.; Sparrey, Carolyn J.; Camisa, William; Fischer, Jason; Leasure, Jeremi; Buckley, Jennifer; Nout-Lomas, Yvette S.; Rosenzweig, Ephron S.; Moseanko, Rod; Strand, Sarah; Hawbecker, Stephanie; Lemoy, Marie-Josee; Haefeli, Jenny; Ma, Xiaokui; Nielson, Jessica L.; Edgerton, V.R.; Ferguson, Adam R.; Tuszynski, Mark H.

    2016-01-01

    Abstract The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies. PMID:26788611

  14. Can non-human primates serve as models for investigating dengue disease pathogenesis?

    PubMed Central

    Clark, Kristina B.; Onlamoon, Nattawat; Hsiao, Hui-Mien; Perng, Guey C.; Villinger, Francois

    2013-01-01

    Dengue Virus (DV) infects between 50 and 100 million people globally, with public health costs totaling in the billions. It is the causative agent of dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), vector-borne diseases that initially predominated in the tropics. Due to the expansion of its mosquito vector, Aedes spp., DV is increasingly becoming a global problem. Infected individuals may present with a wide spectrum of symptoms, spanning from a mild febrile to a life-threatening illness, which may include thrombocytopenia, leucopenia, hepatomegaly, hemorrhaging, plasma leakage and shock. Deciphering the underlining mechanisms responsible for these symptoms has been hindered by the limited availability of animal models that can induce classic human pathology. Currently, several permissive non-human primate (NHP) species and mouse breeds susceptible to adapted DV strains are available. Though virus replication occurs in these animals, none of them recapitulate the cardinal features of human symptomatology, with disease only occasionally observed in NHPs. Recently our group established a DV serotype 2 intravenous infection model with the Indian rhesus macaque, which reliably produced cutaneous hemorrhages after primary virus exposure. Further manipulation of experimental parameters (virus strain, immune cell expansion, depletion, etc.) can refine this model and expand its relevance to human DF. Future goals include applying this model to elucidate the role of pre-existing immunity upon secondary infection and immunopathogenesis. Of note, virus titers in primates in vivo and in vitro, even with our model, have been consistently 1000-fold lower than those found in humans. We submit that an improved model, capable of demonstrating severe pathogenesis may only be achieved with higher virus loads. Nonetheless, our DV coagulopathy disease model is valuable for the study of select pathomechanisms and testing DV drug and vaccine candidates

  15. Modeling Zika plasma viral dynamics in non-human primates: insights into viral pathogenesis and antiviral strategies

    SciTech Connect

    Best, Katharine; Guedj, Jeremie; Madelain, Vincent; de Lamballerie, Xavier; L, So-Yonim; Osuna, Christa E; Whitney, James; Perelson, Alan S.

    2016-10-24

    The recent outbreak of Zika virus (ZIKV) has been associated with fetal abnormalities and neurological complications, prompting global concern. Here we present the first mathematical analysis of the within-host dynamics of plasma ZiKV burden in a non-human primate model, allowing for characterization of the growth and clearance of ZIKV within an individual macaque.

  16. Protective Potential of Antioxidant Enzymes as Vaccines for Schistosomiasis in a Non-Human Primate Model

    PubMed Central

    Carvalho-Queiroz, Claudia; Nyakundi, Ruth; Ogongo, Paul; Rikoi, Hitler; Egilmez, Nejat K.; Farah, Idle O.; Kariuki, Thomas M.; LoVerde, Philip T.

    2015-01-01

    produced high levels of cytokines and chemokines in response to crude and recombinant antigens compared with controls. All together, these data demonstrate the potential of antioxidants as a vaccine in a non-human primate model. PMID:26082781

  17. A non-human primate model of radiation-induced cachexia

    PubMed Central

    Cui, Wanchang; Bennett, Alexander W.; Zhang, Pei; Barrow, Kory R.; Kearney, Sean R.; Hankey, Kim G.; Taylor-Howell, Cheryl; Gibbs, Allison M.; Smith, Cassandra P.; MacVittie, Thomas J.

    2016-01-01

    Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20–25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease. PMID:27029502

  18. A non-human primate model of radiation-induced cachexia.

    PubMed

    Cui, Wanchang; Bennett, Alexander W; Zhang, Pei; Barrow, Kory R; Kearney, Sean R; Hankey, Kim G; Taylor-Howell, Cheryl; Gibbs, Allison M; Smith, Cassandra P; MacVittie, Thomas J

    2016-03-31

    Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

  19. Perceptual learning in a non-human primate model of artificial vision

    PubMed Central

    Killian, Nathaniel J.; Vurro, Milena; Keith, Sarah B.; Kyada, Margee J.; Pezaris, John S.

    2016-01-01

    Visual perceptual grouping, the process of forming global percepts from discrete elements, is experience-dependent. Here we show that the learning time course in an animal model of artificial vision is predicted primarily from the density of visual elements. Three naïve adult non-human primates were tasked with recognizing the letters of the Roman alphabet presented at variable size and visualized through patterns of discrete visual elements, specifically, simulated phosphenes mimicking a thalamic visual prosthesis. The animals viewed a spatially static letter using a gaze-contingent pattern and then chose, by gaze fixation, between a matching letter and a non-matching distractor. Months of learning were required for the animals to recognize letters using simulated phosphene vision. Learning rates increased in proportion to the mean density of the phosphenes in each pattern. Furthermore, skill acquisition transferred from trained to untrained patterns, not depending on the precise retinal layout of the simulated phosphenes. Taken together, the findings suggest that learning of perceptual grouping in a gaze-contingent visual prosthesis can be described simply by the density of visual activation. PMID:27874058

  20. Non-human primate models of PD to test novel therapies.

    PubMed

    Morissette, Marc; Di Paolo, Thérèse

    2017-04-08

    Non-human primate (NHP) models of Parkinson disease show many similarities with the human disease. They are very useful to test novel pharmacotherapies as reviewed here. The various NHP models of this disease are described with their characteristics including the macaque, the marmoset, and the squirrel monkey models. Lesion-induced and genetic models are described. There is no drug to slow, delay, stop, or cure Parkinson disease; available treatments are symptomatic. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-Dopa) still remains the gold standard symptomatic treatment of Parkinson. However, involuntary movements termed L-Dopa-induced dyskinesias appear in most patients after chronic treatment and may become disabling. Dyskinesias are very difficult to manage and there is only amantadine approved providing only a modest benefit. In this respect, NHP models have been useful to seek new drug targets, since they reproduce motor complications observed in parkinsonian patients. Therapies to treat motor symptoms in NHP models are reviewed with a discussion of their translational value to humans. Disease-modifying treatments tested in NHP are reviewed as well as surgical treatments. Many biochemical changes in the brain of post-mortem Parkinson disease patients with dyskinesias are reviewed and compare well with those observed in NHP models. Non-motor symptoms can be categorized into psychiatric, autonomic, and sensory symptoms. These symptoms are present in most parkinsonian patients and are already installed many years before the pre-motor phase of the disease. The translational usefulness of NHP models of Parkinson is discussed for non-motor symptoms.

  1. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

    PubMed Central

    Uchida, Azusa; Sasaguri, Hiroki; Kimura, Nobuyuki; Tajiri, Mio; Ohkubo, Takuya; Ono, Fumiko; Sakaue, Fumika; Kanai, Kazuaki; Hirai, Takashi; Sano, Tatsuhiko; Shibuya, Kazumoto; Kobayashi, Masaki; Yamamoto, Mariko; Yokota, Shigefumi; Kubodera, Takayuki; Tomori, Masaki; Sakaki, Kyohei; Enomoto, Mitsuhiro; Hirai, Yukihiko; Kumagai, Jiro; Yasutomi, Yasuhiro; Mochizuki, Hideki; Kuwabara, Satoshi; Uchihara, Toshiki; Mizusawa, Hidehiro

    2012-01-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and

  2. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43.

    PubMed

    Uchida, Azusa; Sasaguri, Hiroki; Kimura, Nobuyuki; Tajiri, Mio; Ohkubo, Takuya; Ono, Fumiko; Sakaue, Fumika; Kanai, Kazuaki; Hirai, Takashi; Sano, Tatsuhiko; Shibuya, Kazumoto; Kobayashi, Masaki; Yamamoto, Mariko; Yokota, Shigefumi; Kubodera, Takayuki; Tomori, Masaki; Sakaki, Kyohei; Enomoto, Mitsuhiro; Hirai, Yukihiko; Kumagai, Jiro; Yasutomi, Yasuhiro; Mochizuki, Hideki; Kuwabara, Satoshi; Uchihara, Toshiki; Mizusawa, Hidehiro; Yokota, Takanori

    2012-03-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and

  3. The Contribution of Non-human Primate Models to the Development of Human Vaccines

    PubMed Central

    Rivera-Hernandez, Tania; Carnathan, Diane G.; Moyle, Peter M.; Toth, Istvan; West, Nicholas P.; Young, Paul L.; Silvestri, Guido; Walker, Mark J.

    2015-01-01

    The nonhuman primates (NHPs) model in biomedical research has contributed to the study of human infectious, autoimmune, oncogenic, and neurological diseases. This review focuses on the importance of NHP models in vaccine development for tuberculosis, pertussis, Dengue, group A streptococcus (Streptococcus pyogenes) infection, HIV infection, and certain diseases in the elderly (influenza, for example). From understanding disease pathogenesis and mechanisms of protection, to assessing vaccine safety and efficacy, we discuss selected cases where the importance of the use of NHP models is highlighted. PMID:25549702

  4. [Ecotourism disturbances to non-human primates].

    PubMed

    Fan, Peng-Lai; Xiang, Zuo-Fu

    2013-02-01

    In tandem with economic growth and rising living conditions, ecotourism has increasingly gained popularity among the Chinese public. Non-human primates, as charismatic animals and the closest relatives of human beings, have shown a strong affinity in attracting the general public and raising money, and for that reason a variety of monkey parks, valleys, and islands are becoming increasingly popular in China. Though successful in raising a substantial sum of money for the managing agency of a nature reserve, there may be negative impacts on monkey groups used in ecotourism. Here, to establish effective guards for non-human primates involved in ecotourism, we present a review on tourism disturbance and summarize the negative impacts on behavioral patterns, reproduction, and health condition of animals.

  5. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.

    PubMed

    Rose, Destanie R; Careaga, Milo; Van de Water, Judy; McAllister, Kim; Bauman, Melissa D; Ashwood, Paul

    2016-11-19

    Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing of MIA.An additional three non-treated animals were used as controls. The offspring were followed until 4 years of age, with blood collected at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function. Induced responses from peripheral immune cells were measured using multiplex assays.At one year of age, MIA exposed offspring displayed elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α at baseline and following stimulation. At four years of age, the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13. Throughout this time period, the offspring of MIA treated dams exhibited altered behavioral phenotypes including increased stereotyped behaviors. During the first two years, stereotyped behaviors were associated with innate cytokine production

  6. Promoting Autoimmune Diabetes in Non-Human Primates

    DTIC Science & Technology

    2014-04-01

    cannot adequately maintain glucose homeostasis to completely prevent diabetic complications like cardiovascular diseases, nephropathy , retinopathy and...0417 TITLE: Promoting Autoimmune Diabetes in Non-Human Primates PRINCIPAL INVESTIGATOR: Massimo Trucco, M.D...11 January 2014 4. TITLE AND SUBTITLE Promoting Autoimmune Diabetes in Non-Human Primates 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11

  7. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey, Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of

  8. Chronic Alcohol Abuse and HIV Disease Progression: Studies with the Non-Human Primate Model

    PubMed Central

    Amedee, Angela M.; Nichols, Whitney A.; Robichaux, Spencer; Bagby, Gregory J.; Nelson, Steve

    2015-01-01

    The populations at risk for HIV infection, as well as those living with HIV, overlap with populations that engage in heavy alcohol consumption. Alcohol use has been associated with high-risk sexual behavior and an increased likelihood of acquiring HIV, as well as poor outcome measures of disease such as increased viral loads and declines in CD4+ T lymphocytes among those living with HIV-infections. It is difficult to discern the biological mechanisms by which alcohol use affects the virus:host interaction in human populations due to the numerous variables introduced by human behavior. The rhesus macaque infected with simian immunodeficiency virus has served as an invaluable model for understanding HIV disease and transmission, and thus, provides an ideal model to evaluate the effects of chronic alcohol use on viral infection and disease progression in a controlled environment. In this review, we describe the different macaque models of chronic alcohol consumption and summarize the studies conducted with SIV and alcohol. Collectively, they have shown that chronic alcohol consumption results in higher levels of plasma virus and alterations in immune cell populations that potentiate SIV replication. They also demonstrate a significant impact of chronic alcohol use on SIV-disease progression and survival. These studies highlight the utility of the rhesus macaque in deciphering the biological effects of alcohol on HIV disease. Future studies with this well-established model will address the biological influence of alcohol use on susceptibility to HIV, as well as the efficacy of anti-retroviral therapy. PMID:25053367

  9. Overlesioned hemiparkinsonian non human primate model: correlation between clinical, neurochemical and histochemical changes.

    PubMed

    Oiwa, Yoshitsugu; Eberling, Jamie L; Nagy, Dea; Pivirotto, Phillip; Emborg, Marina E; Bankiewicz, Krys S

    2003-09-01

    Monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been widely used as animal models of Parkinson's disease (PD). Depending on the method of administration different PD models can be developed. Systemic (iv, sc.) MPTP administration can induce an advanced parkinsonian syndrome. However, systemic administration may require intensive animal care after neurotoxin administration, as well as repeated high doses of MPTP to avoid spontaneous recovery. Unilateral intracarotid artery (ICA) MPTP administration induces a stable hemiparkinsonian syndrome, with the advantage of allowing the animal to groom and feed itself and having a control side in the same animal. However, this unilateral syndrome lacks the bilateral characteristics of advanced PD. Bilateral ICA administration can induce a reliable bilateral syndrome but inherent is the risk of severely impairing the animals and leaving them unable to maintain themselves. This report analyzed the PD model induced by administration of unilateral ICA and subsequent intravenous injections of MPTP in rhesus monkeys. The combined method of MPTP administration induces an advanced stable parkinsonian syndrome, in which the ICA injection of MPTP initiates the parkinsonian syndrome primarily in one hemisphere and the subsequent iv. doses (administered as needed) further deplete the dopamine (DA) system to induce a bilateral lesion in a shorter period of time, with fewer side effects. We studied the relationships between the behavioral, biochemical and histochemical changes related to the combined MPTP treatments to further characterize this model. The monkeys were categorized as presenting mild (stage 2) or moderate (stage 3) parkinsonism based on a parkinsonian rating scale. Postmortem biochemical analysis showed massive DA reduction equally in the caudate nucleus and putamen ipsilateral to ICA MPTP infusion, with varying degrees of DA preservation in the contralateral striatum. Differences between stage 2

  10. Mechanical Design and Analysis of a Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates.

    PubMed

    Sparrey, Carolyn J; Salegio, Ernesto A; Camisa, William; Tam, Horace; Beattie, Michael S; Bresnahan, Jacqueline C

    2016-06-15

    Non-human primate (NHP) models of spinal cord injury better reflect human injury and provide a better foundation to evaluate potential treatments and functional outcomes. We combined finite element (FE) and surrogate models with impact data derived from in vivo experiments to define the impact mechanics needed to generate a moderate severity unilateral cervical contusion injury in NHPs (Macaca mulatta). Three independent variables (impactor displacement, alignment, and pre-load) were examined to determine their effects on tissue level stresses and strains. Mechanical measures of peak force, peak displacement, peak energy, and tissue stiffness were analyzed as potential determinants of injury severity. Data generated from FE simulations predicted a lateral shift of the spinal cord at high levels of compression (>64%) during impact. Submillimeter changes in mediolateral impactor position over the midline increased peak impact forces (>50%). Surrogate cords established a 0.5 N pre-load protocol for positioning the impactor tip onto the dural surface to define a consistent dorsoventral baseline position before impact, which corresponded with cerebrospinal fluid displacement and entrapment of the spinal cord against the vertebral canal. Based on our simulations, impactor alignment and pre-load were strong contributors to the variable mechanical and functional outcomes observed in in vivo experiments. Peak displacement of 4 mm after a 0.5N pre-load aligned 0.5-1.0 mm over the midline should result in a moderate severity injury; however, the observed peak force and calculated peak energy and tissue stiffness are required to properly characterize the severity and variability of in vivo NHP contusion injuries.

  11. Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in non-human primates

    PubMed Central

    Makris, Angela; Yeung, Kristen R; Lim, Shirlene M; Sunderland, Neroli; Heffernan, Scott; Thompson, John F; Iliopoulos, Jim; Killingsworth, Murray C; Yong, Jim; Xu, Bei; Ogle, Robert F; Thadhani, Ravi; Karumanchi, S. Ananth; Hennessy, Annemarie

    2016-01-01

    An imbalance in the angiogenesis axis during pregnancy manifests as clinical preeclampsia due to endothelial dysfunction. Circulating sFLT-1 (soluble fms-like tyrosine kinase 1) increases and PlGF (placental growth factor) reduces prior to and during disease. We investigated the clinical and biochemical effects of replenishing the reduced circulating PlGF with recombinant human PlGF (rhPlGF) and thus restoring the angiogenic balance. Hypertensive proteinuria was induced in a non-human primate (Papio hamadryas) by uterine artery ligation at 136 days gestation (of an 182 day pregnancy). Two weeks after uteroplacental ischemia (UPI), rhPlGF (rhPlGF, n=3) or normal saline (control, n=4) was administered by subcutaneous injection (100μg/kg/day) for 5 days. Blood pressure (BP) was monitored by intra-arterial radiotelemetry, sFLT-1 and PlGF by ELISA. UPI resulted in experimental preeclampsia evidenced by increased BP, proteinuria and endotheliosis on renal biopsy and elevated sFLT-1. PlGF significantly reduced after UPI. rhPlGF reduced SBP in the treated group (-5.2mmHg+0.8mmHg;from 132.6+6.6mmHg to 124.1+7.6mmHg) compared to an increase in SBP in controls (6.5mmHg+3mmHg; from 131.3+1.5mmHg to 138.6+1.5mmHg). Proteinuria reduced in the treated group (-72.7±55.7mg/mmol) but increased in the control group. Circulating sFLT-1 was not affected by the administration of PlGF, however a reduction in placental sFLT-1 mRNA expression was demonstrated. There was no significant difference in the weights or lengths of the neonates in the rhPlGF or control group, however, this study was not designed to assess fetal safety or outcomes. Increasing circulating PlGF by the administration of rhPlGF improves clinical parameters in a primate animal model of experimental preeclampsia. PMID:27091894

  12. Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration.

    PubMed

    Porrino, Linda J; Beveridge, Thomas J R; Smith, Hilary R; Nader, Michael A

    2016-05-01

    Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure.

  13. High dose of plasmid IL-15 inhibits immune responses in an influenza non-human primates immunogenicity model

    SciTech Connect

    Yin Jiangmei; Dai Anlan; Laddy, Dominick J.; Yan Jian; Arango, Tatiana; Khan, Amir S.; Lewis, Mark G.; Andersen, Hanne; Kutzler, Michele A.; Draghia-Akli, Ruxandra; Weiner, David B.; Boyer, Jean D.

    2009-10-10

    Interleukin (IL)-15, is a cytokine that is important for the maintenance of long-lasting, high-avidity T cell response to invading pathogens and has, therefore, been used in vaccine and therapeutic platforms as an adjuvant. In addition to pure protein delivery, plasmids encoding the IL-15 gene have been utilized. However, it is critical to determine the appropriate dose to maximize the adjuvanting effects. We immunized rhesus macaques with different doses of IL-15 expressing plasmid in an influenza non-human primate immunogenicity model. We found that co-immunization of rhesus macaques with a Flu DNA-based vaccine and low doses of plasmid encoding macaque IL-15 enhanced the production of IFN-gamma (0.5 mg) and the proliferation of CD4{sup +} and CD8{sup +} T cells, as well as T{sub CM} levels in proliferating CD8{sup +} T cells (0.25 mg). Whereas, high doses of IL-15 (4 mg) decrease the production of IFN-gamma and the proliferation of CD4{sup +} and CD8{sup +} T cells and T{sub CM} levels in the proliferating CD4{sup +} and CD8{sup +} T cells. In addition, the data of hemagglutination inhibition (HI) antibody titer suggest that although not significantly different, there appears to be a slight increase in antibodies at lower doses of IL-15. Importantly, however, the higher doses of IL-15 decrease the antibody levels significantly. This study demonstrates the importance of optimizing DNA-based cytokine adjuvants.

  14. Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model.

    PubMed

    League-Pascual, James C; Lester-McCully, Cynthia M; Shandilya, Shaefali; Ronner, Lukas; Rodgers, Louis; Cruz, Rafael; Peer, Cody J; Figg, William D; Warren, Katherine E

    2017-03-13

    The blood-brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1 mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration-time curves for CSF and plasma (AUCCSF:plasma). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32-57) and 22 (20-41)%, respectively. Although maximum TMZ drug concentration in the CSF (Cmax) was lower after intranasal

  15. Microgravity Flight: Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1995-01-01

    Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey, Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of

  16. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of

  17. Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

    PubMed Central

    Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo; Redhi, Godfrey H; Auber, Alessia; Secci, Maria E; Mascia, Paola; Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Chefer, Svetlana I; Barnes, Chanel; Yasar, Sevil; Piomelli, Daniele; Goldberg, Steven R

    2015-01-01

    Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose–response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell—consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement. PMID:25754762

  18. Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator

    NASA Astrophysics Data System (ADS)

    Connolly, Allison T.; Muralidharan, Abirami; Hendrix, Claudia; Johnson, Luke; Gupta, Rahul; Stanslaski, Scott; Denison, Tim; Baker, Kenneth B.; Vitek, Jerrold L.; Johnson, Matthew D.

    2015-12-01

    Objective. Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach. Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results. LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects’ limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. Significance. This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject’s symptomatology.

  19. Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.

    PubMed

    Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo; Redhi, Godfrey H; Auber, Alessia; Secci, Maria E; Mascia, Paola; Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Chefer, Svetlana I; Barnes, Chanel; Yasar, Sevil; Piomelli, Daniele; Goldberg, Steven R

    2015-08-01

    Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.

  20. Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator

    PubMed Central

    Connolly, Allison T; Muralidharan, Abirami; Hendrix, Claudia; Johnson, Luke; Gupta, Rahul; Stanslaski, Scott; Denison, Tim; Baker, Kenneth B; Vitek, Jerrold L; Johnson, Matthew D

    2016-01-01

    Objective Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10–30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects’ limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30–60 s, but there was no correlation with beta band power. Significance This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject’s symptomatology. PMID:26469737

  1. Non-human primate models of alcohol-related phenotypes: the influence of genetic and environmental factors.

    PubMed

    Barr, Christina S

    2013-01-01

    Because of their complex social structures, behaviors, and genetic similarities to humans, nonhuman primates are useful for studying how genetic factors influence alcohol consumption. The neurobiological systems that influence addiction vulnerability may do so by acting on alcohol response, reward pathways, behavioral dyscontrol, and vulnerability to stress and anxiety. Rhesus macaques show individual differences in alcohol response and temperament, and such differences are influenced by genetic variants that are similar functionally to those present in humans. Genes at which variation moderates these phenotypes include those encoding monoamine oxidase A (MAOA-LPR), the serotonin transporter (HTTLPR), corticotropin releasing hormone (CRH-248C/T and -2232 C/G), Neuropeptide Y (NPY-1002 T/G), and the μ-opioid receptor (OPRM1 C77G). These provide opportunities for modeling how genetic and environmental factors (i.e., stress, individual's sex, or alcohol exposure) interact to influence alcohol consumption. Studies in primates may also reveal selective factors have driven maintenance or fixation of alleles that increase risk for alcohol use disorders in modern humans.

  2. DNA sequencing of 13 cytokine gene fragments of Aotus infulatus and Saimiri sciureus, two non-human primate models for malaria.

    PubMed

    Alves, F A; Souza, M T; Gonçalves, E C; Schneider, M P C; Marinho, A M; Muniz, J A P C; Fragoso, S P; Krieger, M A; Goldenberg, S; Daniel-Ribeiro, C T; Carvalho, L J M

    2010-12-01

    Aotus and Saimiri are non-human primate models recommended by the World Health Organization for experimental studies in malaria, especially for vaccine pre-clinical trials. However, research using these primates is hindered by the lack of specific reagents to evaluate immune responses to infection or vaccination. As a step toward developing molecular tools for cytokine expression studies in these species, primer pairs for 18 cytokine gene fragments were designed based on human DNA sequences and used to amplify the corresponding genes in Aotus infulatus and Saimiri sciureus genomic DNA samples. IFNγ, TNFα, LTA, IL2, IL3, IL4, IL5, IL6, IL10, IL12, IL13, CSF2 and TGFβ2 gene fragments were amplified and sequenced. Primer pairs for IL8, IL17, IL18, IL27 and MIF failed to generate amplification products. When compared to the available corresponding human and non-human primate sequences, most--except IL3 and IL4--showed identity degrees above 90%. Small variations in sequence can help to explain the failure to amplify certain genes or the amplification only at lower annealing temperatures as compared to human DNA samples for several primer pairs. The sequences made available provide the basis for designing molecular tools such as primers for real time PCR specific for A. infulatus and/or S. sciureus. The nucleotide sequences reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned accession numbers DQ985386 to DQ985389, DQ989356 to DQ989369, FJ89020 to FJ89024, and FJ89029.

  3. Striatal Volume Differences Between Non-human and Human Primates

    PubMed Central

    Yin, Dali; Valles, Francisco E.; Fiandaca, Massimo S.; Forsayeth, John; Larson, Paul; Starr, Phillip; Bankiewicz, Krystof S.

    2009-01-01

    Convection-enhanced delivery (CED) has recently entered the clinic and represents a promising new delivery option for targeted gene therapy in Parkinson’s disease (PD). The prime stereotactic target for the majority of recent gene therapy clinical trials has been the human putamen. The stereotactic delivery of therapeutic agents into putamen (or other subcortical structures) via CED remains problematic due to the difficulty in knowing what volume of therapeutic agent to deliver. Preclinical studies in non-human primates (NHP) offer a way to model treatment strategies prior to clinical trials. Understanding more accurately the volumetric differences in striatum, especially putamen, between NHP and humans is essential in predicting convective volume parameters in human clinical trials. In this study, magnetic resonance images (MRI) were obtained for volumetric measurements of striatum (putamen and caudate nucleus) and whole brain from 11 PD patients, 13 aged healthy human subjects, as well as 8 parkinsonian and 30 normal NHP. The human brain is 13–18 times larger than the monkey brain. However, this ratio is significantly smaller for striatum (5.7–6.5), caudate nucleus (4.6–6.6) and putamen (4.4–6.6). Size and species of the monkeys used for this comparative study are responsible for differences in ratios for each structure between monkeys and humans. This volumetric ratio may have important implications in the design of clinical therapies for PD and Huntington’s disease and should be considered when local therapies such as gene transfer, local protein administration or cellular replacement are translated based on non-human primate research. PMID:18809434

  4. Examination of the Safety of Pediatric Vaccine Schedules in a Non-Human Primate Model: Assessments of Neurodevelopment, Learning, and Social Behavior

    PubMed Central

    Curtis, Britni; Liberato, Noelle; Rulien, Megan; Morrisroe, Kelly; Kenney, Caroline; Yutuc, Vernon; Ferrier, Clayton; Marti, C. Nathan; Mandell, Dorothy; Burbacher, Thomas M.; Sackett, Gene P.

    2015-01-01

    Background In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal-containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today. Objectives The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model. Methods We administered vaccines to six groups of infant male rhesus macaques (n = 12–16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles–mumps–rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age-matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate. Results We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors. Conclusions This comprehensive 5-year case–control study, which closely examined

  5. Oscillatory correlates of memory in non-human primates.

    PubMed

    Jutras, Michael J; Buffalo, Elizabeth A

    2014-01-15

    The ability to navigate through our environment, explore with our senses, track the passage of time, and integrate these various components to form the experiences which make up our lives is shared among humans and animals. The use of animal models to study memory, coupled with electrophysiological techniques that permit the direct measurement of neural activity as memories are formed and retrieved, has provided a wealth of knowledge about these mechanisms. Here, we discuss current knowledge regarding the specific role of neural oscillations in memory, with particular emphasis on findings derived from non-human primates. Some of these findings provide evidence for the existence in the primate brain of mechanisms previously identified only in rodents and other lower mammals, while other findings suggest parallels between memory-related activity and processes observed in other cognitive modalities, including attention and sensory perception. Taken together, these results provide insight into how network activity may be organized to promote memory formation, and suggest that key aspects of this activity are similar across species, providing important information about the organization of human memory.

  6. Comparing adjuvanted H28 and modified vaccinia virus ankara expressingH28 in a mouse and a non-human primate tuberculosis model.

    PubMed

    Billeskov, Rolf; Christensen, Jan P; Aagaard, Claus; Andersen, Peter; Dietrich, Jes

    2013-01-01

    Here we report for the first time on the immunogenicity and protective efficacy of a vaccine strategy involving the adjuvanted fusion protein "H28" (consisting of Ag85B-TB10.4-Rv2660c) and Modified Vaccinia Virus Ankara expressing H28. We show that a heterologous prime-boost regimen involving priming with H28 in a Th1 adjuvant followed by boosting with H28 expressed by MVA (H28/MVA28) induced the highest percentage of IFN-γ expressing T cells, the highest production of IFN-γ per single cell and the highest induction of CD8 T cells compared to either of the vaccines given alone. In contrast, in mice vaccinated with adjuvanted recombinant H28 alone (H28/H28) we observed the highest production of IL-2 per single cell and the highest frequency of antigen specific TNF-α/IL-2 expressing CD4 T cells pre and post infection. Interestingly, TNF-α/IL-2 expressing central memory-like CD4 T cells showed a significant positive correlation with protection at week 6 post infection, whereas the opposite was observed for post infection CD4 T cells producing only IFN-γ. Moreover, as a BCG booster vaccine in a clinically relevant non-human primate TB model, the H28/H28 vaccine strategy induced a slightly more prominent reduction of clinical disease and pathology for up to one year post infection compared to H28/MVA28. Taken together, our data showed that the adjuvanted subunit and MVA strategies led to different T cell subset combinations pre and post infection and that TNF-α/IL-2 double producing but not IFN-γ single producing CD4 T cell subsets correlated with protection in the mouse TB model. Moreover, our data demonstrated that the H28 vaccine antigen was able to induce strong protection in both a mouse and a non-human primate TB model.

  7. Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders.

    PubMed

    Watson, Karli K; Platt, Michael L

    2012-07-30

    The autism spectrum disorders (ASDs) arise from a diverse array of genetic and environmental origins that disrupt the typical developmental trajectory of neural connectivity and synaptogenesis. ASDs are marked by dysfunctional social behavior and cognition, among other deficits. Greater understanding of the biological substrates of typical social behavior in animal models will further our understanding of the etiology of ASDs. Despite the precision and tractability of molecular genetics models of ASDs in rodents, these organisms lack the complexity of human social behavior, thus limiting their impact on understanding ASDs to basic mechanisms. Non-human primates (NHPs) provide an attractive, complementary model for ASDs, due in part to the complexity and dynamics of social structures, reliance on vision for social signaling, and deep homology in brain circuitry mediating social behavior and reward. This knowledge is based on a rich literature, compiled over 50 years of observing primate behavior in the wild, which, in the case of rhesus macaques, is complemented by a large body of research characterizing neuronal activity during cognitive behavior. Several recent developments in this field are directly relevant to ASDs, including how the brain represents the perceptual features of social stimuli, how social information influences attention processes in the brain, and how the value of social interaction is computed. Because the symptoms of ASDs may represent extreme manifestations of traits that vary in intensity within the general population, we will additionally discuss ways in which nonhuman primates also show variation in social behavior and reward sensitivity. In cases where variation in species-typical behavior is analogous to similar variations in human behavior, we believe that study of the neural circuitry underlying this variation will provide important insights into the systems-level mechanisms contributing to ASD pathology.

  8. Characterization of interleukin-8 receptors in non-human primates

    SciTech Connect

    Alvarez, V.; Coto, E.; Gonzalez-Roces, S.; Lopez-Larrea, C.

    1996-09-01

    Interleukin-8 is a chemokine with a potent neutrophil chemoatractant activity. In humans, two different cDNAs encoding human IL8 receptors designated IL8RA and IL8RB have been cloned. IL8RA binds IL8, while IL8RB binds IL8 as well as other {alpha}-chemokines. Both human IL8Rs are encoded by two genes physically linked on chromosome 2. The IL8RA and IL8RB genes have open reading frames (ORF) lacking introns. By direct sequencing of the polymerase chain reaction products, we sequenced the IL8R genes of cell lines from four non-human primates: chimpanzee, gorilla, orangutan, and macaca. The IL8RB encodes an ORF in the four non-human primates, showing 95%-99% similarity to the human IL8RB sequence. The IL8RA homologue in gorilla and chimpanzee consisted of two ORF 98%-99% identical to the human sequence. The macaca and orangutan IL8RA homologues are pseudogenes: a 2 base pair insertion generated a sequence with several stop codons. In addition, we describe the physical linkage of these genes in the four non-human primates and discuss the evolutionary implications of these findings. 25 refs., 5 figs., 3 tabs.

  9. Real-Time Ophthalmoscopic Findings of Super-Selective Intra-Ophthalmic Artery Chemotherapy in a Non-Human Primate Model

    PubMed Central

    Wilson, Matthew W.; Jackson, John S.; Phillips, Blanca X.; Buchanan, Jacquelyn; Frase, Sharon; Wang, Fan; Steinle, Jena J.; Stewart, Clinton F.; Mandrell, Timothy D.; Haik, Barrett G.; Williams, J. Scott

    2012-01-01

    Objectives To report real-time ophthalmoscopic findings during super-selective intra-ophthalmic artery chemotherapy (SSIOAC) in a non-human primate (NHP) model. Methods Six adult male Rhesus macaques (Macacca mulatta) were randomly assigned into one of two treatment cohorts; MEL treated with 5 mg/30 mL melphalan, and CBP treated with 30 mg/30 mL carboplatin. Each animal underwent three separate SSIOAC procedures at three-week intervals. Digital retinal images were obtained during each infusion. Intravenous fluorescein angiography was performed immediately after each procedure. Results All SSIOAC procedures were successfully completed. Toxicities were equally distributed between drug cohorts. Systemic toxicities included mild bone marrow suppression in all animals and anorexia in one. One animal had greater than 50% narrowing of the treated ophthalmic artery after its second infusion. All 18 procedures (100%) resulted in pulsatile optic nerve and choroid blanching, retinal artery narrowing, and retinal edema. Retinal artery sheathing was found during 17 (of 18, 94%) procedures, and retinal artery precipitates were seen in 10 (of 18, 56%). Choroidal hypoperfusion (18 of 18, 100%) was seen by fluorescein angiogram. Conclusions Real-time ophthalmic investigations are useful and, in our NHP model, indicate prevalent, acute ocular vascular toxicities during SSIOAC. Clinical Relevance Real-time retinal imaging is feasible in an NHP model of SSIOAC. Application to SSIOAC in children may shed insight into reported vascular toxicities. PMID:22084215

  10. Path to the clinic: Assessment of iPSC-based cell therapies in vivo in a non-human primate model

    PubMed Central

    Wu, Chuanfeng; Guo, Vicky; Pittaluga, Stefania; Nicolae, Alina; Donahue, Robert E.; Metzger, Mark E.; Price, Sandra D.; Uchida, Naoya; Kuznetsov, Sergei A.; Kilts, Tina; Li, Li; Robey, Pamela G.; Dunbar, Cynthia E.

    2014-01-01

    Summary Induced pluripotent stem cell (iPSC)-based cell therapies have a great potential for regenerative medicine, but are also potentially associated with tumorigenic risks. Current rodent models are not the optimal predictors of efficiency and safety for clinical application. Therefore, we developed a clinically relevant non-human primate model to assess the tumorigenic potential and in vivo efficacy of both undifferentiated and differentiated iPSCs in the autologous settings without immunosuppression. Undifferentiated autologous iPSCs indeed formed mature teratomas in a dose-dependent manner. However, tumor formation was accompanied by an inflammatory reaction. On the other hand, iPSC-derived mesodermal stromal-like cells formed new bone in vivo without any evidence of teratoma formation. We therefore show for the first time in a large animal model that closely resembles human physiology that undifferentiated autologous iPSCs form teratomas, and that iPSC-derived progenitor cells can give rise to a functional tissue in vivo. PMID:24835994

  11. Whisper-like behavior in a non-human primate.

    PubMed

    Morrison, Rachel; Reiss, Diana

    2013-01-01

    In humans, whispering has evolved as a counteractive strategy against eavesdropping. Some evidence for whisper-like behavior exists in a few other species, but has not been reported in non-human primates. We discovered the first evidence of whisper-like behavior in a non-human primate, the cotton-top tamarin (Saguinus oedipus), in the course of investigating their use of human-directed mobbing calls. We exposed a family of captive cotton-top tamarins to a supervisor who previously elicited a strong mobbing response. Simultaneous audio-video recordings documented the animals' behavioral and vocal responses in the supervisor's presence and absence. Rather than exhibiting a mobbing response and producing loud human-directed mobbing calls, the tamarins exhibited other anti-predator behaviors and produced low amplitude vocalizations that initially eluded our detection. A post-hoc analysis of the data was conducted to test a new hypothesis-the tamarins were reducing the amplitude of their vocalizations in the context of exposure to a potential threat. Consistent with whisper-like behavior, the amplitude of the tamarins' vocalizations was significantly reduced only in the presence of the supervisor. Due to its subtle properties, this phenomenon may have eluded detection in this species. Increasing evidence of whisper-like behavior in non-human species suggests that such low amplitude signaling may represent a convergence in a communication strategy amongst highly social and cooperative species.

  12. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease

    PubMed Central

    Hallett, Penelope J; Deleidi, Michela; Astradsson, Arnar; Smith, Gaynor A.; Cooper, Oliver; Osborn, Teresia; Sundberg, Maria; Moore, Michele A.; Perez-Torres, Eduardo; Brownell, Anna-Liisa; Schumacher, James; Spealman, Roger D.; Isacson, Ole

    2015-01-01

    Summary Autologous transplantation of patient-specific iPSC-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration of long-term efficacy, feasibility and safety of iPSC-derived dopamine neurons in non human primate models will be an important step in clinical development of cell therapy. Here, we analyzed cynomolgus monkey (CM) iPSC-derived midbrain dopamine neurons for up to 2 years following autologous transplantation in a Parkinson's disease (PD) model. In one animal, with the most successful protocol, we found that unilateral engraftment of CM-iPSCs could provide a gradual onset of functional motor improvement contralateral to the side of dopamine neuron transplantation, and increased motor activity, without a need for immunosuppression. Post-mortem analyses demonstrated robust survival of midbrain-like dopaminergic neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD. PMID:25732245

  13. [Diversity and development of positional behavior in non-human primates].

    PubMed

    Zhang, Jing; Qi, Xiao-Guang; Zhang, Kan; Zhang, Pei; Guo, Song-Tao; Wei, Wei; Li, Bao-Guo

    2012-10-01

    In long-term evolution, wildlife in general and primates in particular have formed specific patterns of behavior to adapt to a diverse variety of habitat environments. Current research on positional behavior in non-human primates has been found to explain a great deal about primate adaptability diversification, ecology, anatomy and evolution. Here, we summarize the noted classifications and differences in seasonal, site-specific and sex-age positional behaviors while also reviewing the development and status of non-human primate positional behavior research. This review is intended to provide reference for the future research of non-human primates and aid in further research on behavioral ecology of primates.

  14. Suffixation influences receivers' behaviour in non-human primates

    PubMed Central

    Coye, Camille; Ouattara, Karim; Zuberbühler, Klaus; Lemasson, Alban

    2015-01-01

    Compared to humans, non-human primates have very little control over their vocal production. Nonetheless, some primates produce various call combinations, which may partially offset their lack of acoustic flexibility. A relevant example is male Campbell's monkeys (Cercopithecus campbelli), which give one call type (‘Krak’) to leopards, while the suffixed version of the same call stem (‘Krak-oo’) is given to unspecific danger. To test whether recipients attend to this suffixation pattern, we carried out a playback experiment in which we broadcast naturally and artificially modified suffixed and unsuffixed ‘Krak’ calls of male Campbell's monkeys to 42 wild groups of Diana monkeys (Cercopithecus diana diana). The two species form mixed-species groups and respond to each other's vocalizations. We analysed the vocal response of male and female Diana monkeys and overall found significantly stronger vocal responses to unsuffixed (leopard) than suffixed (unspecific danger) calls. Although the acoustic structure of the ‘Krak’ stem of the calls has some additional effects, subject responses were mainly determined by the presence or the absence of the suffix. This study indicates that suffixation is an evolved function in primate communication in contexts where adaptive responses are particularly important. PMID:25925101

  15. The Effects of a Calorie Reduced Diet on Periodontal Inflammation and Disease in a Non Human Primate Model

    PubMed Central

    Branch-Mays, Grishondra L.; Dawson, Dolphus R.; Gunsolley, John C.; Reynolds, Mark A.; Ebersole, Jeffrey L.; Novak, Karen F.; Mattison, Julie A.; Ingram, Donald K.; Novak, M. John

    2008-01-01

    Background Low calorie diets are commonplace for reducing body weight. However, no information is available on the effects of a reduced calorie diet on periodontal inflammation and disease. The purpose of this study was to evaluate the clinical effects of a long term calorie restricted diet (CR) on periodontitis in an animal model of periodontitis. Methods Periodontitis was induced in 55 young, healthy, adult rhesus monkeys (Macaca mulatta) by tying 2.0 silk ligatures at the gingival margins of maxillary premolar/molar teeth. Animals on a CR diet (30% CR; n=23) were compared to ad libitum diet controls (n=32). Clinical measures including plaque (PLI), probing pocket depth (PD), clinical attachment level (CAL), modified Gingival Index (GI) and bleeding on probing (BOP) were taken at baseline and 1, 2, and 3 months after ligature placement. Results Significant effects of CR were observed on the development of inflammation and the progression of periodontal destruction in this model. When compared to controls, CR resulted in a significant reduction in ligature induced GI (p<0.0001), BOP (p<0.0015), PD (p<0.0016), and CAL (p<0.0038). When viewed over time, periodontal destruction, as measured by CAL, progressed significantly more slowly in the CR animals than in the controls (p<0.001). Conclusions These clinical findings are consistent with available evidence that CR has anti-inflammatory effects. Moreover, these experimental findings are the first observations that CR dampens the inflammatory response and reduces active periodontal breakdown associated with an acute microbial challenge. PMID:18597600

  16. Individualized recording chambers for non-human primate neurophysiology

    PubMed Central

    McAndrew, R.M.; VanGilder, J.L. Lingo; Naufel, S.N.; Tillery, S.I. Helms

    2012-01-01

    While neural recording chambers for non-human primates can be purchased commercially, these generic chambers do not contour to the animal’s skull. In order to seal gaps, a cap of dental acrylic (methyl methacrylate) is often applied around the chamber. There are multiple disadvantages associated with this method. Applying acrylic delays and further complicates surgical procedure, and overheating during the curing process can cause damage to the bone. Post-surgery, acrylic margins can give rise to bacterial growth and infection. Here we describe a method to develop custom implants which conform to the individual’s skull, thereby eliminating the need for acrylic. This method shortens surgery time and significantly improves the hygiene of chamber margins. PMID:22498201

  17. Mediodorsal thalamus and cognition in non-human primates.

    PubMed

    Baxter, Mark G

    2013-01-01

    Several recent studies in non-human primates have provided new insights into the role of the medial thalamus in different aspects of cognitive function. The mediodorsal nucleus of the thalamus (MD), by virtue of its connectivity with the frontal cortex, has been implicated in an array of cognitive functions. Rather than serving as an engine or relay for the prefrontal cortex, this area seems to be more specifically involved in regulating plasticity and flexibility of prefrontal-dependent cognitive functions. Focal damage to MD may also exacerbate the effects of damage to other subcortical relays. Thus, a wide range of distributed circuits and cognitive functions may be disrupted from focal damage within the medial thalamus (for example as a consequence of stroke or brain injury). Conversely, this region may make an interesting target for neuromodulation of cognitive function via deep brain stimulation or related methods, in conditions associated with dysfunction of these neural circuits.

  18. Characterization of a 2016 Clinical Isolate of Zika Virus in Non-human Primates.

    PubMed

    Li, Xiao-Feng; Dong, Hao-Long; Huang, Xing-Yao; Qiu, Ye-Feng; Wang, Hong-Jiang; Deng, Yong-Qiang; Zhang, Na-Na; Ye, Qing; Zhao, Hui; Liu, Zhong-Yu; Fan, Hang; An, Xiao-Ping; Sun, Shi-Hui; Gao, Bo; Fa, Yun-Zhi; Tong, Yi-Gang; Zhang, Fu-Chun; Gao, George F; Cao, Wu-Chun; Shi, Pei-Yong; Qin, Cheng-Feng

    2016-10-01

    Animal models are critical to understand disease and to develop countermeasures for the ongoing epidemics of Zika virus (ZIKV). Here we report a non-human primate model using a 2016 contemporary clinical isolate of ZIKV. Upon subcutaneous inoculation, rhesus macaques developed fever and viremia, with robust excretion of ZIKV RNA in urine, saliva, and lacrimal fluid. Necropsy of two infected animals revealed that systematic infections involving central nervous system and visceral organs were established at the acute phrase. ZIKV initially targeted the intestinal tracts, spleen, and parotid glands, and retained in spleen and lymph nodes till 10days post infection. ZIKV-specific immune responses were readily induced in all inoculated animals. The non-human primate model described here provides a valuable platform to study ZIKV pathogenesis and to evaluate vaccine and therapeutics.

  19. Enumeration of Objects and Substances in Non-Human Primates: Experiments with Brown Lemurs ("Eulemur Fulvus")

    ERIC Educational Resources Information Center

    Mahajan, Neha; Barnes, Jennifer L.; Blanco, Marissa; Santos, Laurie R.

    2009-01-01

    Both human infants and adult non-human primates share the capacity to track small numbers of objects across time and occlusion. The question now facing developmental and comparative psychologists is whether similar mechanisms give rise to this capacity across the two populations. Here, we explore whether non-human primates' object tracking…

  20. Investigation of sleep–wake rhythm in non-human primates without restraint during data collection

    PubMed Central

    Ishikawa, Akiyoshi; Sakai, Keita; Maki, Takehiro; Mizuno, Yuri; Niimi, Kimie; Oda, Yasuhiro; Takahashi, Eiki

    2016-01-01

    To understand sleep mechanisms and develop treatments for sleep disorders, investigations using animal models are essential. The sleep architecture of rodents differs from that of diurnal mammals including humans and non-human primates. Sleep studies have been conducted in non-human primates; however, these sleep assessments were performed on animals placed in a restraint chair connected via the umbilical area to the recording apparatus. To avoid restraints, cables, and other stressful apparatuses and manipulations, telemetry systems have been developed. In the present study, sleep recordings in unrestrained cynomolgus monkeys (Macaca fascicularis) and common marmoset monkeys (Callithrix jacchus) were conducted to characterize normal sleep. For the analysis of sleep–wake rhythms in cynomolgus monkeys, telemetry electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG) signals were used. For the analysis of sleep–wake rhythms in marmosets, telemetry EEG and EOG signals were used. Both monkey species showed monophasic sleep patterns during the dark phase. Although non-rapid eye movement (NREM) deep sleep showed higher levels at the beginning of the dark phase in cynomolgus monkeys, NREM deep sleep rarely occurred during the dark phase in marmosets. Our results indicate that the use of telemetry in non-human primate models is useful for sleep studies, and that the different NREM deep sleep activities between cynomolgus monkeys and common marmoset monkeys are useful to examine sleep functions. PMID:27760892

  1. African Non-Human Primates Host Diverse Enteroviruses

    PubMed Central

    Mombo, Illich Manfred; Lukashev, Alexander N.; Bleicker, Tobias; Brünink, Sebastian; Berthet, Nicolas; Maganga, Gael D.; Durand, Patrick; Arnathau, Céline; Boundenga, Larson; Ngoubangoye, Barthélémy; Boué, Vanina; Liégeois, Florian; Ollomo, Benjamin; Prugnolle, Franck; Drexler, Jan Felix; Drosten, Christian; Renaud, François; Rougeron, Virginie; Leroy, Eric

    2017-01-01

    Enteroviruses (EVs) belong to the family Picornaviridae and are responsible for mild to severe diseases in mammals including humans and non-human primates (NHP). Simian EVs were first discovered in the 1950s in the Old World Monkeys and recently in wild chimpanzee, gorilla and mandrill in Cameroon. In the present study, we screened by PCR EVs in 600 fecal samples of wild apes and monkeys that were collected at four sites in Gabon. A total of 32 samples were positive for EVs (25 from mandrills, 7 from chimpanzees, none from gorillas). The phylogenetic analysis of VP1 and VP2 genes showed that EVs identified in chimpanzees were members of two human EV species, EV-A and EV-B, and those identified in mandrills were members of the human species EV-B and the simian species EV-J. The identification of two novel enterovirus types, EV-B112 in a chimpanzee and EV-B113 in a mandrill, suggests these NHPs could be potential sources of new EV types. The identification of EV-B107 and EV90 that were previously found in humans indicates cross-species transfers. Also the identification of chimpanzee-derived EV110 in a mandrill demonstrated a wide host range of this EV. Further research of EVs in NHPs would help understanding emergence of new types or variants, and evaluating the real risk of cross-species transmission for humans as well for NHPs populations. PMID:28081564

  2. Role of non-human primates in malaria vaccine development: Memorandum from a WHO Meeting*

    PubMed Central

    1988-01-01

    This Memorandum discusses the coordination and standardization of malaria vaccine research in non-human primates to encourage optimum use of the available animals in experiments that are fully justified both scientifically and ethically. The requirements for experimentation in non-human primates, the availability of suitable animals for malaria vaccine studies, and the criteria for testing candidate vaccines are considered. The policy and legislation relevant to the use of non-human primates in biomedical research are also briefly discussed. The Memorandum concludes with eight recommendations. PMID:3266112

  3. PET neuroimaging studies of [18F]CABS13 in a double transgenic mouse model of Alzheimer’s disease and non-human primates

    PubMed Central

    Liang, Steven H.; Holland, Jason P.; Stephenson, Nickeisha A.; Kassenbrock, Alina; Rotstein, Benjamin H.; Daignault, Cory P.; Lewis, Rebecca; Collier, Lee; Hooker, Jacob M.; Vasdev, Neil

    2016-01-01

    Fluorine-18 labeled 2-fluoro-8-hydroxyquinoline ([18F]CABS13) is a promising positron emission tomography (PET) radiopharmaceutical based on a metal chelator developed to probe the “metal hypothesis of Alzheimer’s disease”. Herein, a practical radiosynthesis of [18F]CABS13 was achieved by radiofluorination followed by deprotection of an O-benzyloxymethyl group. Automated production and formulation of [18F]CABS13 resulted in 19 ± 5% uncorrected radiochemical yield, relative to starting [18F]fluoride, with ≥95% chemical and radiochemical purities, and high specific activity (>2.5 Ci/μmol) within 80 minutes. Temporal PET neuroimaging studies were carried out in female transgenic B6C3- Tg(APPswe,PSEN1dE9)85Dbo/J (APP/PS1) and age-matched wild-type (WT) B6C3F1/J control mice at 3, 7 and 10 months of age. [18F]CABS13 showed an overall higher uptake and retention of radioactivity in the central nervous system of APP/PS1 mice versus WT mice with increasing age. However, PET/magnetic resonance imaging in normal non-human primates revealed that the tracer had low uptake in the brain and rapid formation of a hydrophilic radiometabolite. Identification of more metabolically stable 18F-hydroxyquinolines that can be readily accessed by the radiochemical strategy presented herein is underway. PMID:25776827

  4. Cloning of non-human primates: the road "less traveled by".

    PubMed

    Sparman, Michelle L; Tachibana, Masahito; Mitalipov, Shoukhrat M

    2010-01-01

    Early studies on cloning of non-human primates by nuclear transfer utilized embryonic blastomeres from preimplantation embryos which resulted in the reproducible birth of live offspring. Soon after, the focus shifted to employing somatic cells as a source of donor nuclei (somatic cell nuclear transfer, SCNT). However, initial efforts were plagued with inefficient nuclear reprogramming and poor embryonic development when standard SCNT methods were utilized. Implementation of several key SCNT modifications was critical to overcome these problems. In particular, a non-invasive method of visualizing the metaphase chromosomes during enucleation was developed to preserve the reprogramming capacity of monkey oocytes. These modifications dramatically improved the efficiency of SCNT, yielding high blastocyst development in vitro. To date, SCNT has been successfully used to derive pluripotent embryonic stem cells (ESCs) from adult monkey skin fibroblasts. These remarkable advances have the potential for development of human autologous ESCs and cures for many human diseases. Reproductive cloning of nonhuman primates by SCNT has not been achieved yet. We have been able to establish several pregnancies with SCNT embryos which, so far, did not progress to term. In this review, we summarize the approaches, obstacles and accomplishments of SCNT in a non-human primate model.

  5. Development of translational preclinical models in substance abuse: Effects of cocaine administration on cocaine choice in humans and non-human primates.

    PubMed

    Foltin, Richard W; Haney, Margaret; Rubin, Eric; Reed, Stephanie C; Vadhan, Nehal; Balter, Rebecca; Evans, Suzette M

    2015-07-01

    Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how 'free' doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose-response function for cocaine self-administration (10 choices of 0.0125-0.1mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large 'free' self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates.

  6. Using non-human primates to benefit humans: research and organ transplantation.

    PubMed

    Shaw, David; Dondorp, Wybo; de Wert, Guido

    2014-11-01

    Emerging biotechnology may soon allow the creation of genetically human organs inside animals, with non-human primates (henceforth simply "primates") and pigs being the best candidate species. This prospect raises the question of whether creating organs in primates in order to then transplant them into humans would be more (or less) acceptable than using them for research. In this paper, we examine the validity of the purported moral distinction between primates and other animals, and analyze the ethical acceptability of using primates to create organs for human use.

  7. Protection of Non-Human Primates against Rabies with an Adenovirus Recombinant Vaccine

    PubMed Central

    Xiang, Z.Q.; Greenberg, L.; Ertl, H. C.; Rupprecht, C.E.

    2014-01-01

    Rabies remains a major neglected global zoonosis. New vaccine strategies are needed for human rabies prophylaxis. A single intramuscular immunization with a moderate dose of an experimental chimpanzee adenovirus (Ad) vector serotype SAd-V24, also termed AdC68, expressing the rabies virus glycoprotein, resulted in sustained titers of rabies virus neutralizing antibodies and protection against a lethal rabies virus challenge infection in a non-human primate model. Taken together, these data demonstrate the safety, immunogenicity, and efficacy of the recombinant Ad-rabies vector for further consideration in human clinical trials. PMID:24503087

  8. [Symbol-based communication in non-human primates: a C. S. Peirce's semiotic analysis].

    PubMed

    Queiroz, João

    2003-12-01

    Are (or were) there any other symbolic species? This question has been addressed by researchers from many different fields and is responsible for a historical controversy on the existence of a threshold between "symbolic creatures" vs "simple forms of language creatures". According to the mainstream ethology and comparative psychology only the Homo sapiens is cognitively equiped to produce and interpret symbols. Here, I introduce an empirically testable model of symbolic semiosis ("symbolic action of sign") supported by C.S.Peirce logical-phenomenological theory of categories. I suggest that a specific sign-user pattern of behavior, observed in non-human primate communication, indicate a transition from indexical to symbolic semiosis.

  9. Biokinetics of plutonium-238 injected in non-human primates

    NASA Astrophysics Data System (ADS)

    Chelidze, Nino

    Seventeen intravenously injected monkey data were analyzed using PowerBasic and SAAM II softwares. The study was divided into three parts. In the first part SAAM II predictions were compared with those calculated by Birchall algorithm based on the ICRP 67 systemic model for plutonium. In the second part SAAM II simulations were performed and compared for two representations of systemic model for plutonium: the ICRP 67 model and the Leggett model. In the third part, optimization of transfer rates suggested by ICRP 67 and Leggett models were attempted by solving each monkey case independently. The Birchall algorithm and SAAM II predicted values coincide with each other for all data presented: blood, urine and feces. Unfortunately, these predictions do not coincide with the measurement values. Plutonium activity in liver is about 50% of the injected activity. The uptake of plutonium in liver in primates seems to be close to the assumption of equal distribution of 45% plutonium in liver and skeleton in humans. For longer sacrificed monkeys we have prolonged liver retention compared to plutonium liver retention in humans. Pu retention in urine and blood has been simulated based on the ICRP 67 and Leggett models respectively and plotted against the measured data points to acquire the understanding of the models with respect to reality. Pu activity was also evaluated in liver and skeleton at the time of the sacrifice for both models and compared with the autopsy measurements for individual cases. Optimization of transfer rates suggested in the ICRP 67 and Leggett models was attempted. Default transfer rates were varied to improve the fits to the data and predict activities in the liver and skeleton at the time of death has been carried out in SAAM II. Good fits for the individual cases were obtained successfully, however, consistency among parameters from case to case was not observed.

  10. No monkey business: why studying NK cells in non-human primates pays off.

    PubMed

    Hong, Henoch S; Rajakumar, Premeela A; Billingsley, James M; Reeves, R Keith; Johnson, R Paul

    2013-01-01

    Human NK (hNK) cells play a key role in mediating host immune responses against various infectious diseases. For practical reasons, the majority of the data on hNK cells has been generated using peripheral blood lymphocytes. In contrast, our knowledge of NK cells in human tissues is limited, and not much is known about developmental pathways of hNK cell subpopulations in vivo. Although research in mice has elucidated a number of fundamental features of NK cell biology, mouse, and hNK cells significantly differ in their subpopulations, functions, and receptor repertoires. Thus, there is a need for a model that is more closely related to humans and yet allows experimental manipulations. Non-human primate models offer numerous opportunities for the study of NK cells, including the study of the role of NK cells after solid organ and stem cell transplantation, as well as in acute viral infection. Macaque NK cells can be depleted in vivo or adoptively transferred in an autologous system. All of these studies are either difficult or unethical to carry out in humans. Here we highlight recent advances in rhesus NK cell research and their parallels in humans. Using high-throughput transcriptional profiling, we demonstrate that the human CD56(bright) and CD56(dim) NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques. Thus, the use of non-human primate models offers the potential to substantially advance hNK cell research.

  11. Nicotinic receptors in non-human primates: analysis of genetic and functional conservation with humans

    PubMed Central

    Shorey-Kendrick, Lyndsey E.; Ford, Matthew M.; Allen, Daicia C.; Kuryatov, Alexander; Lindstrom, Jon; Wilhelm, Larry; Grant, Kathleen A.; Spindel, Eliot R.

    2015-01-01

    Nicotinic acetylcholine receptors (nAChRs) are highly conserved between humans and non-human primates. Conservation exists at the level of genomic structure, protein structure and epigenetics. Overall homology of nAChRs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. In addition to conservation at the protein level, there is high conservation of genomic structure in terms of intron and exon size and placement of CpG sites that play a key role in epigenetic regulation. Analysis of single nucleotide polymorphisms (SNPs) shows that while the majority of SNPs are not conserved between humans and macaques, some functional polymorphisms are. Most significantly, cynomolgus monkeys express a similar α5 nAChR Asp398Asn polymorphism to the human α5 Asp398Asn polymorphism that has been linked to greater nicotine addiction and smoking related disease. Monkeys can be trained to readily self-administer nicotine, and in an initial study we have demonstrated that cynomolgus monkeys bearing the α5 D398N polymorphism show a reduced behavioral sensitivity to oral nicotine and tend to consume it in a different pattern when compared to wild-type monkeys. Thus the combination of highly homologous nAChR, higher cortical functions and capacity for complex training makes non-human primates a unique model to study in vivo functions of nicotinic receptors. In particular, primate studies on nicotine addiction and evaluation of therapies to prevent or overcome nicotine addiction are likely to be highly predictive of treatment outcomes in humans. PMID:25661700

  12. The active metabolite of prasugrel, R-138727, improves cerebral blood flow and reduces cerebral infarction and neurologic deficits in a non-human primate model of acute ischaemic stroke.

    PubMed

    Sugidachi, Atsuhiro; Mizuno, Makoto; Ohno, Kousaku; Jakubowski, Joseph A; Tomizawa, Atsuyuki

    2016-10-05

    Previously, we showed preventive effects of prasugrel, a P2Y12 antagonist, in a non-human primate model of thrombotic middle cerebral artery occlusion (MCAO); however, it remains unclear if P2Y12 inhibition after MCAO reduces cerebral injury and dysfunction. Here we investigated the effects of R-138727, the major active metabolite of prasugrel, on ex vivo platelet aggregation at 5min, 15min, 60min, and 24h after administration to non-human primates (n=3). A single intravenous dose of R-138727 (0.03-0.3mg/kg) resulted in significant and sustained dose-related effects on platelets for up to 24h. R-138727 was administered 1h after MCAO induction, and its effects on thrombosis, cerebral infarction, and neurological deficits were determined (n=8-10). R-138727 (0.3mg/kg) significantly increased total patency rate of the MCA (P=0.0211). Although there was no effect on the patency rate before R-138727 dosing (P=0.3975), it increased 1h after dosing (P=0.0114). R-138727 significantly reduced total ischaemic infarction volumes (P=0.0147), including those of basal ganglia (P=0.0028), white matter (P=0.0393), and haemorrhagic infarction (P=0.0235). Additionally, treatment with R-138727 reduced overall neurological deficits (P=0.0019), including the subcategories of consciousness (P=0.0042), sensory system (P=0.0045), motor system (P=0.0079) and musculoskeletal coordination (P=0.0082). These findings support the possible utility of P2Y12 inhibition during early-onset MCAO to limit the progression and degree of cerebral ischaemia and infarction and also associated neurological deficits.

  13. Citrulline as a biomarker in the non-human primate total- and partial-body irradiation models: correlation of circulating citrulline to acute and prolonged gastrointestinal injury

    PubMed Central

    Jones, Jace W.; Bennett, Alexander; Carter, Claire L.; Tudor, Gregory; Hankey, Kim G.; Farese, Ann M.; Booth, Catherine; MacVittie, Thomas J.; Kane, Maureen A.

    2015-01-01

    The use of plasma citrulline as a biomarker for acute and prolonged gastrointestinal injury via exposure to total- and partial-body irradiation (6 MV LINAC-derived photons; 0.80 Gy min−1) in nonhuman primate models was investigated. The irradiation exposure covered gastrointestinal injuries spanning lethal, mid-lethal, and sub-lethal doses. The acute gastrointestinal injury was assessed via measurement of plasma citrulline and small intestinal histopathology over the first 15 days following radiation exposure and included total-body irradiation at 13.0 Gy, 10.5 Gy, and 7.5 Gy and partial-body irradiation at 11.0 Gy with 5% bone marrow sparing. The dosing schemes of 7.5 Gy total-body irradiation and 11.0 Gy partial-body irradiation included time points out to day 60 and day 180, respectively, which allowed for correlation of plasma citrulline to prolonged gastrointestinal injury and survival. Plasma citrulline values were radiation-dependent for all radiation doses under consideration with nadir values ranging from 63–80 % lower than radiation-naïve NHP plasma. The nadir values were observed at day 5 to 7 post irradiation. Longitudinal plasma citrulline profiles demonstrated prolonged gastrointestinal injury resulting from acute high-dose irradiation had long lasting effects on enterocyte function. Moreover, plasma citrulline did not discriminate between total-body or partial-body irradiation over the first 15 days following irradiation and was not predictive of survival based on the radiation models considered herein. PMID:26425904

  14. The translational value of non-human primates in preclinical research on infection and immunopathology.

    PubMed

    't Hart, Bert A; Bogers, Willy M; Haanstra, Krista G; Verreck, Frank A; Kocken, Clemens H

    2015-07-15

    The immune system plays a central role in the defense against environmental threats - such as infection with viruses, parasites or bacteria - but can also be a cause of disease, such as in the case of allergic or autoimmune disorders. In the past decades the impressive development of biotechnology has provided scientists with biological tools for the development of highly selective treatments for the different types of disorders. However, despite some clear successes the translation of scientific discoveries into effective treatments has remained challenging. The often-disappointing predictive validity of the preclinical animal models that are used in the selection of the most promising vaccine or drug candidates is the Achilles heel in the therapy development process. This publication summarizes the relevance and usage of non-human primates as pre-clinical model in infectious and autoimmune diseases, in particular for biologicals, which due to their high species-specificity are inactive in lower species.

  15. Hominin geographical range dynamics and relative brain size: Do non-human primates provide a good analogy?

    PubMed

    MacDonald, Katharine; Smaers, Jeroen B; Steele, James

    2015-10-01

    We use climatic and satellite remote sensing data to characterize environmental seasonality in the geographical ranges of extant non-human primates in order to assess the effect of relative brain size on tolerance of more seasonal habitats. Demonstration of such an effect in living non-human primates could provide a comparative framework for modeling hominin dispersals and geographical range dynamics in the Pliocene and Pleistocene. Our analyses found no such effect: there are neither positive nor negative correlations between relative brain size and either geographical range size or the average and range of values for environmental seasonality, whether analysed at the level of all primates, or within parvorders (strepsirrhine, catarrhine, platyrrhine). Independent analyses by other researchers comparing feeding behaviour and ecology at individual primate study sites demonstrate that in seasonal environments, the year-round metabolic costs of maintaining a relatively large brain are met by adaptive behavioural/dietary strategies. However, consistent with our own results, those comparative studies found that there was no overall association, whether positive or negative, between 'raw' environmental seasonality and primate relative brain size. We must therefore look elsewhere for a comparative model of hominin geographical range dynamics in the Pleistocene.

  16. Protection of non-human primates against rabies with an adenovirus recombinant vaccine

    SciTech Connect

    Xiang, Z.Q.; Greenberg, L.; Ertl, H.C.; Rupprecht, C.E.

    2014-02-15

    Rabies remains a major neglected global zoonosis. New vaccine strategies are needed for human rabies prophylaxis. A single intramuscular immunization with a moderate dose of an experimental chimpanzee adenovirus (Ad) vector serotype SAd-V24, also termed AdC68, expressing the rabies virus glycoprotein, resulted in sustained titers of rabies virus neutralizing antibodies and protection against a lethal rabies virus challenge infection in a non-human primate model. Taken together, these data demonstrate the safety, immunogenicity, and efficacy of the recombinant Ad-rabies vector for further consideration in human clinical trials. - Highlights: • Pre-exposure vaccination with vaccine based on a chimpanzee derived adenovirus protects against rabies. • Protection is sustained. • Protection is achieved with single low-dose of vaccine given intramuscularly. • Protection is not affected by pre-existing antibodies to common human serotypes of adenovirus.

  17. Studying brain functions with mesoscopic measurements: advances in electrocorticography for non-human primates

    PubMed Central

    Fukushima, Makoto; Chao, Zenas C.

    2015-01-01

    Our brain is organized in a modular structure. Information in different modalities is processed within distinct cortical areas. However, individual cortical areas cannot enable complex cognitive functions without interacting with other cortical areas. Electrocorticography (ECoG) has recently become an important tool for studying global network activity across cortical areas in animal models. With stable recordings of electrical field potentials from multiple cortical areas, ECoG provides an opportunity to systematically study large-scale cortical activity at a mesoscopic spatiotemporal resolution under various experimental conditions. Recent developments in thin, flexible ECoG electrodes permit recording field potentials from not only gyral but intrasulcal cortical surfaces. Our review here focuses on the recent advances of ECoG applications to non-human primates. PMID:25889531

  18. Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts

    PubMed Central

    Chong, James J.H.; Yang, Xiulan; Don, Creighton W.; Minami, Elina; Liu, Yen-Wen; Weyers, Jill J; Mahoney, William M.; Van Biber, Benjamin; Cook, Savannah M.; Palpant, Nathan J; Gantz, Jay; Fugate, James A.; Muskheli, Veronica; Gough, G. Michael; Vogel, Keith W.; Astley, Cliff A.; Hotchkiss, Charlotte E.; Baldessari, Audrey; Pabon, Lil; Reinecke, Hans; Gill, Edward A.; Nelson, Veronica; Kiem, Hans-Peter; Laflamme, Michael A.; Murry, Charles E.

    2014-01-01

    Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure 1 by providing human cardiomyocytes to support heart regeneration 2. Studies of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in small animal models have shown favorable effects of this treatment 3–7. It remains unknown, however, whether clinical scale hESC-CMs transplantation is feasible, safe or can provide large-scale myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (>1 billion cells/batch) and cryopreserved with good viability. Using a non-human primate (NHP) model of myocardial ischemia-reperfusion, we show that that cryopreservation and intra-myocardial delivery of 1 billion hESC-CMs generates significant remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a three-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small animal models 7, non-fatal ventricular arrhythmias were observed in hESC-CM engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome. PMID:24776797

  19. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.

    PubMed

    Chong, James J H; Yang, Xiulan; Don, Creighton W; Minami, Elina; Liu, Yen-Wen; Weyers, Jill J; Mahoney, William M; Van Biber, Benjamin; Cook, Savannah M; Palpant, Nathan J; Gantz, Jay A; Fugate, James A; Muskheli, Veronica; Gough, G Michael; Vogel, Keith W; Astley, Cliff A; Hotchkiss, Charlotte E; Baldessari, Audrey; Pabon, Lil; Reinecke, Hans; Gill, Edward A; Nelson, Veronica; Kiem, Hans-Peter; Laflamme, Michael A; Murry, Charles E

    2014-06-12

    Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

  20. Neurophysiology and Neuroanatomy of Reflexive and Voluntary Saccades in Non-Human Primates

    ERIC Educational Resources Information Center

    Johnston, Kevin; Everling, Stefan

    2008-01-01

    A multitude of cognitive functions can easily be tested by a number of relatively simple saccadic eye movement tasks. This approach has been employed extensively with patient populations to investigate the functional deficits associated with psychiatric disorders. Neurophysiological studies in non-human primates performing the same tasks have…

  1. Attenuation correction for the large non-human primate brain imaging using microPET

    NASA Astrophysics Data System (ADS)

    Naidoo-Variawa, S.; Lehnert, W.; Kassiou, M.; Banati, R.; Meikle, S. R.

    2010-04-01

    Assessment of the biodistribution and pharmacokinetics of radiopharmaceuticals in vivo is often performed on animal models of human disease prior to their use in humans. The baboon brain is physiologically and neuro-anatomically similar to the human brain and is therefore a suitable model for evaluating novel CNS radioligands. We previously demonstrated the feasibility of performing baboon brain imaging on a dedicated small animal PET scanner provided that the data are accurately corrected for degrading physical effects such as photon attenuation in the body. In this study, we investigated factors affecting the accuracy and reliability of alternative attenuation correction strategies when imaging the brain of a large non-human primate (papio hamadryas) using the microPET Focus 220 animal scanner. For measured attenuation correction, the best bias versus noise performance was achieved using a 57Co transmission point source with a 4% energy window. The optimal energy window for a 68Ge transmission source operating in singles acquisition mode was 20%, independent of the source strength, providing bias-noise performance almost as good as for 57Co. For both transmission sources, doubling the acquisition time had minimal impact on the bias-noise trade-off for corrected emission images, despite observable improvements in reconstructed attenuation values. In a [18F]FDG brain scan of a female baboon, both measured attenuation correction strategies achieved good results and similar SNR, while segmented attenuation correction (based on uncorrected emission images) resulted in appreciable regional bias in deep grey matter structures and the skull. We conclude that measured attenuation correction using a single pass 57Co (4% energy window) or 68Ge (20% window) transmission scan achieves an excellent trade-off between bias and propagation of noise when imaging the large non-human primate brain with a microPET scanner.

  2. Clinical veterinarian's perspective of non-human primate (NHP) use in drug safety studies.

    PubMed

    Taylor, Katrina

    2010-01-01

    Owing to their size, cost, and availability, the cynomolgus macaque (Macaca fascicularis) has surpassed the rhesus macaque in its use as a non-human primate preclinical model for drug safety studies. There are three major regions where cynomolgus macaques are bred: China, Southeast Asia, and the island of Mauritius. Country of origin of the macaque is important, as disease status and background disease incidence in non-human primates from each of these sites can differ. Once a source of macaque has been decided, careful monitoring of the animal during breeding and by the importing vendor while the animals are in quarantine is important. During vendor quarantine, the animals should be monitored and evaluated for disease, response to tuberculosis testing, retroviral status, and both ecto- and endoparasites. After animals arrive at the test facility, additional quarantine and acclimation are important to ascertain health status further and to reduce stress on the animals, thereby providing a better research model. The type of caging, food, water, and enrichment should be carefully selected to best suit the needs of the study while working within Federal Regulations (i.e., Animal Welfare Act and Good Laboratory Practices). Careful prescreening by performing tests (such as physical, neurologic, and ophthalmologic examinations), complete blood count, biochemical profile, urinanalysis, electrocardiograms, and pulse oximetry is important when selecting the most appropriate animals for the study. After the in-life portion of the study begins, animals that present with clinical signs should be examined and an appropriate treatment course begun while maintaining study objectives. As many commonly used medications have immunomodulatory effects, having an understanding of the mechanism of action of test articles will aid in the appropriate choice of treatment of study animals. A tiered approach to the treatment of these animals is a conservative and usually acceptable approach.

  3. Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson’s Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque

    PubMed Central

    Koprich, James B.; Johnston, Tom H.; Reyes, Gabriela; Omana, Vanessa; Brotchie, Jonathan M.

    2016-01-01

    Recent failures in clinical trials for disease modification in Parkinson’s disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 μl per site, 1.7 x 1012 gp/ml), this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform. PMID:27902767

  4. Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson's Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque.

    PubMed

    Koprich, James B; Johnston, Tom H; Reyes, Gabriela; Omana, Vanessa; Brotchie, Jonathan M

    2016-01-01

    Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 μl per site, 1.7 x 1012 gp/ml), this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform.

  5. Proton Resonance Frequency Chemical Shift Thermometry: Experimental Design and Validation Towards High-Resolution Non-Invasive Temperature Monitoring, and in vivo Experience in a Non-human Primate Model of Acute Ischemic Stroke

    PubMed Central

    Dehkharghani, Seena; Mao, Hui; Howell, Leonard; Zhang, Xiaodong; Pate, K S; Magrath, P R; Tong, Frank; Wei, L; Qiu, D; Fleischer, C; Oshinski, J N

    2016-01-01

    BACKGROUND AND PURPOSE Applications for non-invasive biological temperature monitoring are widespread in biomedicine, and of particular interest in the context of brain temperature regulation, where traditionally costly and invasive monitoring schemes limit their applicability in many settings. Brain thermal regulation therefore remains controversial, motivating the development of non-invasive approaches such as temperature-sensitive NMR phenomena. The purpose of this work was to compare the utility of competing approaches to MR thermometry (MRT) employing proton resonance frequency chemical shift. Three methodologies were tested, hypothesizing the feasibility of a fast and accurate approach to chemical shift thermometry, in a phantom study at 3.0 Tesla. MATERIALS AND METHODS A conventional, paired approach (DIFF-1), an accelerated single-scan approach (DIFF-2), and a new, further accelerated strategy (DIFF-3) were tested. Phantom temperatures were modulated during real-time fiber optic temperature monitoring, with MRT derived simultaneously from temperature-sensitive changes in the water proton chemical shift (~0.01 ppm/°C). MRT was subsequently performed in a series of in vivo non-human primate experiments under physiologic and ischemic conditions testing its reproducibility and overall performance. RESULTS Chemical shift thermometry demonstrated excellent agreement with phantom temperatures for all three approaches (DIFF-1 linear regression R2=0.994, p<0.001, acquisition time 4 min 40 s; DIFF-2 R2=0.996, p<0.001, acquisition time 4 min; DIFF-3 R2=0.998, p<0.001, acquisition time 40 s). CONCLUSION These findings confirm the comparability in performance of three competing approaches MRT, and present in vivo applications under physiologic and ischemic conditions in a primate stroke model. PMID:25655874

  6. Is somnambulism a distinct disorder of humans and not seen in non-human primates?

    PubMed

    Kantha, S S

    2003-01-01

    Though somnambulism (sleepwalking) is a well-recognized sleep disorder in humans, a biomedical literature search in Medline and Primate Literature bibliographic databases showed no publications on sleepwalking in non-human primates. From this finding, two inferences can be made. First is that somnambulism may be present in non-human primates; but due to limitations in expertise and methodological resources as well as narrow focus of research interest, until now researchers have not detected it in wild and/or captive conditions. Second, somnambulism does not exist in non-human primates including apes (chimpanzee, gorilla, orang-utan and gibbon); and thus, it is a unique behavioral disorder present only in humans. It is premature to conclude which of these two inferences is correct. In Jane Goodall's view, sleepwalking behavior is absent in chimpanzees. If further field observations can confirm Goodall's assertion that somnambulism is indeed absent in chimpanzees, it will be of evolutionary and medical interest to know why this parasomnic behavior became established in humans during the past 5.5 million years or so.

  7. Continuities in Emotion Lateralization in Human and Non-Human Primates

    PubMed Central

    Lindell, Annukka K.

    2013-01-01

    Where hemispheric lateralization was once considered an exclusively human trait, it is increasingly recognized that hemispheric asymmetries are evident throughout the animal kingdom. Emotion is a prime example of a lateralized function: given its vital role in promoting adaptive behavior and hence survival, a growing body of research in affective neuroscience is working to illuminate the cortical bases of emotion processing. Presuming that human and non-human primates evolved from a shared ancestor, one would anticipate evidence of organizational continuity in the neural substrate supporting emotion processing. This paper thus reviews research examining the patterns of lateralization for the expression and perception of facial emotion in non-human primates, aiming to determine whether the patterns of hemispheric asymmetry that characterize the human brain are similarly evident in other primate species. As such, this review seeks to enhance understanding of the evolution of hemispheric specialization for emotion, using emotion lateralization in non-human primates as a window through which to view emotion lateralization in humans. PMID:23964230

  8. Are non-human primates capable of rhythmic entrainment? Evidence for the gradual audiomotor evolution hypothesis.

    PubMed

    Merchant, Hugo; Honing, Henkjan

    2013-01-01

    We propose a decomposition of the neurocognitive mechanisms that might underlie interval-based timing and rhythmic entrainment. Next to reviewing the concepts central to the definition of rhythmic entrainment, we discuss recent studies that suggest rhythmic entrainment to be specific to humans and a selected group of bird species, but, surprisingly, is not obvious in non-human primates. On the basis of these studies we propose the gradual audiomotor evolution hypothesis that suggests that humans fully share interval-based timing with other primates, but only partially share the ability of rhythmic entrainment (or beat-based timing). This hypothesis accommodates the fact that non-human primates (i.e., macaques) performance is comparable to humans in single interval tasks (such as interval reproduction, categorization, and interception), but show differences in multiple interval tasks (such as rhythmic entrainment, synchronization, and continuation). Furthermore, it is in line with the observation that macaques can, apparently, synchronize in the visual domain, but show less sensitivity in the auditory domain. And finally, while macaques are sensitive to interval-based timing and rhythmic grouping, the absence of a strong coupling between the auditory and motor system of non-human primates might be the reason why macaques cannot rhythmically entrain in the way humans do.

  9. Viral Kinetics of Primary Dengue Virus Infection in Non-Human Primates: A Systematic Review and Individual Pooled Analysis

    PubMed Central

    Althouse, Benjamin M.; Durbin, Anna P.; Hanley, Kathryn A.; Halstead, Scott B.; Weaver, Scott C.; Cummings, Derek A. T.

    2014-01-01

    Viremia kinetics directly influence the clinical course and transmission dynamics of DENV, but many aspects of viral dynamics remain unknown. Non-human primates (NHP) have been used as a model system for DENV infection for decades. Here, we identify papers with experimentally-infected NHP and estimate the time to- and duration of viremia as well as estimate associations between these and serotype, inoculating dose, viremia assay, and species of NHP. We estimate the time to viremia in rhesus macaques to range from 2.63 to 3.32 days for DENV-2 and -1 and the duration to range from 3.13 to 5.13 days for DENV-4 and -2. We find no differences between non-human primates for time to viremia or duration, and a significant negative relationship between inoculating dose and duration of viremia. These results aide in understanding the transmission dynamics of sylvatic DENV non-human primates, an issue of growing importance as dengue vaccines become available. PMID:24606701

  10. An Evaluation of 20 Years of EU Framework Programme-Funded Immune-Mediated Inflammatory Translational Research in Non-Human Primates.

    PubMed

    Haanstra, Krista G; Jonker, Margreet; 't Hart, Bert A

    2016-01-01

    Aging western societies are facing an increasing prevalence of chronic inflammatory and degenerative diseases for which often no effective treatments exist, resulting in increasing health-care expenditure. Despite high investments in drug development, the number of promising new drug candidates decreases. We propose that preclinical research in non-human primates can help to bridge the gap between drug discovery and drug prescription. Translational research covers various stages of drug development of which preclinical efficacy tests in valid animal models is usually the last stage. Preclinical research in non-human primates may be essential in the evaluation of new drugs or therapies when a relevant rodent model is not available. Non-human primate models for life-threatening or severely debilitating diseases in humans are available at the Biomedical Primate Research Centre (BPRC). These have been instrumental in translational research for several decades. In order to stimulate European health research and innovation from bench to bedside, the European Commission has invested heavily in access to non-human primate research for more than 20 years. BPRC has hosted European users in a series of transnational access programs covering a wide range of research areas with the common theme being immune-mediated inflammatory disorders. We present an overview of the results and give an account of the studies performed as part of European Union Framework Programme (EU FP)-funded translational non-human primate research performed at the BPRC. These data illustrate the value of translational non-human primate research for the development of new therapies and emphasize the importance of EU FP funding in drug development.

  11. An Evaluation of 20 Years of EU Framework Programme-Funded Immune-Mediated Inflammatory Translational Research in Non-Human Primates

    PubMed Central

    Haanstra, Krista G.; Jonker, Margreet; ‘t Hart, Bert A.

    2016-01-01

    Aging western societies are facing an increasing prevalence of chronic inflammatory and degenerative diseases for which often no effective treatments exist, resulting in increasing health-care expenditure. Despite high investments in drug development, the number of promising new drug candidates decreases. We propose that preclinical research in non-human primates can help to bridge the gap between drug discovery and drug prescription. Translational research covers various stages of drug development of which preclinical efficacy tests in valid animal models is usually the last stage. Preclinical research in non-human primates may be essential in the evaluation of new drugs or therapies when a relevant rodent model is not available. Non-human primate models for life-threatening or severely debilitating diseases in humans are available at the Biomedical Primate Research Centre (BPRC). These have been instrumental in translational research for several decades. In order to stimulate European health research and innovation from bench to bedside, the European Commission has invested heavily in access to non-human primate research for more than 20 years. BPRC has hosted European users in a series of transnational access programs covering a wide range of research areas with the common theme being immune-mediated inflammatory disorders. We present an overview of the results and give an account of the studies performed as part of European Union Framework Programme (EU FP)-funded translational non-human primate research performed at the BPRC. These data illustrate the value of translational non-human primate research for the development of new therapies and emphasize the importance of EU FP funding in drug development. PMID:27872622

  12. Strontium-90 Biokinetics from Simulated Wound Intakes in Non-human Primates Compared with Combined Model Predictions from National Council on Radiation Protection and Measurements Report 156 and International Commission on Radiological Protection Publication 67.

    PubMed

    Allen, Mark B; Brey, Richard R; Gesell, Thomas; Derryberry, Dewayne; Poudel, Deepesh

    2016-01-01

    This study had a goal to evaluate the predictive capabilities of the National Council on Radiation Protection and Measurements (NCRP) wound model coupled to the International Commission on Radiological Protection (ICRP) systemic model for 90Sr-contaminated wounds using non-human primate data. Studies were conducted on 13 macaque (Macaca mulatta) monkeys, each receiving one-time intramuscular injections of 90Sr solution. Urine and feces samples were collected up to 28 d post-injection and analyzed for 90Sr activity. Integrated Modules for Bioassay Analysis (IMBA) software was configured with default NCRP and ICRP model transfer coefficients to calculate predicted 90Sr intake via the wound based on the radioactivity measured in bioassay samples. The default parameters of the combined models produced adequate fits of the bioassay data, but maximum likelihood predictions of intake were overestimated by a factor of 1.0 to 2.9 when bioassay data were used as predictors. Skeletal retention was also over-predicted, suggesting an underestimation of the excretion fraction. Bayesian statistics and Monte Carlo sampling were applied using IMBA to vary the default parameters, producing updated transfer coefficients for individual monkeys that improved model fit and predicted intake and skeletal retention. The geometric means of the optimized transfer rates for the 11 cases were computed, and these optimized sample population parameters were tested on two independent monkey cases and on the 11 monkeys from which the optimized parameters were derived. The optimized model parameters did not improve the model fit in most cases, and the predicted skeletal activity produced improvements in three of the 11 cases. The optimized parameters improved the predicted intake in all cases but still over-predicted the intake by an average of 50%. The results suggest that the modified transfer rates were not always an improvement over the default NCRP and ICRP model values.

  13. Isolation and Characterization of Adenoviruses Persistently Shed from the Gastrointestinal Tract of Non-Human Primates

    PubMed Central

    Kryazhimskiy, Sergey; Grant, Rebecca; Calcedo, Roberto; Yuan, Xin; Keough, Martin; Sandhu, Arbans; Wang, Qiang; Medina-Jaszek, C. Angelica; Plotkin, Joshua B.; Wilson, James M.

    2009-01-01

    Adenoviruses are important human pathogens that have been developed as vectors for gene therapies and genetic vaccines. Previous studies indicated that human infections with adenoviruses are self-limiting in immunocompetent hosts with evidence of some persistence in adenoid tissue. We sought to better understand the natural history of adenovirus infections in various non-human primates and discovered that healthy populations of great apes (chimpanzees, bonobos, gorillas, and orangutans) and macaques shed substantial quantities of infectious adenoviruses in stool. Shedding in stools from asymptomatic humans was found to be much less frequent, comparable to frequencies reported before. We purified and fully sequenced 30 novel adenoviruses from apes and 3 novel adenoviruses from macaques. Analyses of the new ape adenovirus sequences (as well as the 4 chimpanzee adenovirus sequences we have previously reported) together with 22 complete adenovirus genomes available from GenBank revealed that (a) the ape adenoviruses could clearly be classified into species corresponding to human adenovirus species B, C, and E, (b) there was evidence for intraspecies recombination between adenoviruses, and (c) the high degree of phylogenetic relatedness of adenoviruses across their various primate hosts provided evidence for cross species transmission events to have occurred in the natural history of B and E viruses. The high degree of asymptomatic shedding of live adenovirus in non-human primates and evidence for zoonotic transmissions warrants caution for primate handling and housing. Furthermore, the presence of persistent and/or latent adenovirus infections in the gut should be considered in the design and interpretation of human and non-human primate studies with adenovirus vectors. PMID:19578438

  14. Distinctiveness enhances long-term event memory in non-human primates, irrespective of reinforcement.

    PubMed

    Lewis, Amy; Call, Josep; Berntsen, Dorthe

    2017-04-13

    Non-human primates are capable of recalling events that occurred as long as 3 years ago, and are able to distinguish between similar events; akin to human memory. In humans, distinctiveness enhances memory for events, however, it is unknown whether the same occurs in non-human primates. As such, we tested three great ape species on their ability to remember an event that varied in distinctiveness. Across three experiments, apes witnessed a baiting event in which one of three identical containers was baited with food. After a delay of 2 weeks, we tested their memory for the location of the baited container. Apes failed to recall the baited container when the event was undistinctive (Experiment 1), but were successful when it was distinctive (Experiment 2), although performance was equally good in a less-distinctive condition. A third experiment (Experiment 3) confirmed that distinctiveness, independent of reinforcement, was a consistent predictor of performance. These findings suggest that distinctiveness may enhance memory for events in non-human primates in the same way as in humans, and provides further evidence of basic similarities between the ways apes and humans remember past events.

  15. Non-human primate FOG develops with advanced parkinsonism induced by MPTP Treatment.

    PubMed

    Revuelta, Gonzalo J; Uthayathas, Subramaniam; Wahlquist, Amy E; Factor, Stewart A; Papa, Stella M

    2012-10-01

    Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD) and other forms of parkinsonism. The anatomical or pathophysiological correlates are poorly understood largely due to the lack of a well-established animal model. Here we studied whether FOG is reproduced in the non-human primate (NHP) model of PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (Genus Macaca, n=29) were examined for the development of FOG, and the leg movements were recorded with accelerometry. The relationships between developing FOG and the animals' characteristics, the MPTP treatments, and the modeled outcomes were determined. In parkinsonian monkeys FOG developed frequently (48%) manifesting similar characteristics to those seen in PD patients. In addition, FOG episodes in the monkey were accompanied by leg trembling with the typical duration (2-10s) and frequency (~7 Hz). The development of NHP FOG was significantly associated with the severity of parkinsonism, as shown by high motor disability scores (≥ 20) and levodopa-induced dyskinesia scores (p=0.01 and p=0.04, respectively). Differences in demographics and MPTP treatments (doses, treatment duration, etc.) had no influence on NHP FOG occurrence, with the exception of gender that showed FOG predominance in males (p=0.03). The unique features of FOG in PD can be replicated in severely parkinsonian macaques, and this represents the first description of a FOG animal model.

  16. Primate Drum Kit: A System for Studying Acoustic Pattern Production by Non-Human Primates Using Acceleration and Strain Sensors

    PubMed Central

    Ravignani, Andrea; Olivera, Vicente Matellán; Gingras, Bruno; Hofer, Riccardo; Hernández, Carlos Rodríguez; Sonnweber, Ruth-Sophie; Fitch, W. Tecumseh

    2013-01-01

    The possibility of achieving experimentally controlled, non-vocal acoustic production in non-human primates is a key step to enable the testing of a number of hypotheses on primate behavior and cognition. However, no device or solution is currently available, with the use of sensors in non-human animals being almost exclusively devoted to applications in food industry and animal surveillance. Specifically, no device exists which simultaneously allows: (i) spontaneous production of sound or music by non-human animals via object manipulation, (ii) systematical recording of data sensed from these movements, (iii) the possibility to alter the acoustic feedback properties of the object using remote control. We present two prototypes we developed for application with chimpanzees (Pan troglodytes) which, while fulfilling the aforementioned requirements, allow to arbitrarily associate sounds to physical object movements. The prototypes differ in sensing technology, costs, intended use and construction requirements. One prototype uses four piezoelectric elements embedded between layers of Plexiglas and foam. Strain data is sent to a computer running Python through an Arduino board. A second prototype consists in a modified Wii Remote contained in a gum toy. Acceleration data is sent via Bluetooth to a computer running Max/MSP. We successfully pilot tested the first device with a group of chimpanzees. We foresee using these devices for a range of cognitive experiments. PMID:23912427

  17. Impact of Visual Context on Public Perceptions of Non-Human Primate Performers

    PubMed Central

    Leighty, Katherine A.; Valuska, Annie J.; Grand, Alison P.; Bettinger, Tamara L.; Mellen, Jill D.; Ross, Stephen R.; Boyle, Paul; Ogden, Jacqueline J.

    2015-01-01

    Prior research has shown that the use of apes, specifically chimpanzees, as performers in the media negatively impacts public attitudes of their conservation status and desirability as a pet, yet it is unclear whether these findings generalize to other non-human primates (specifically non-ape species). We evaluated the impact of viewing an image of a monkey or prosimian in an anthropomorphic or naturalistic setting, either in contact with or in the absence of a human. Viewing the primate in an anthropomorphic setting while in contact with a person significantly increased their desirability as a pet, which also correlated with increased likelihood of believing the animal was not endangered. The majority of viewers felt that the primates in all tested images were “nervous.” When shown in contact with a human, viewers felt they were “sad” and “scared”, while also being less “funny.” Our findings highlight the potential broader implications of the use of non-human primate performers by the entertainment industry. PMID:25714101

  18. Impact of visual context on public perceptions of non-human primate performers.

    PubMed

    Leighty, Katherine A; Valuska, Annie J; Grand, Alison P; Bettinger, Tamara L; Mellen, Jill D; Ross, Stephen R; Boyle, Paul; Ogden, Jacqueline J

    2015-01-01

    Prior research has shown that the use of apes, specifically chimpanzees, as performers in the media negatively impacts public attitudes of their conservation status and desirability as a pet, yet it is unclear whether these findings generalize to other non-human primates (specifically non-ape species). We evaluated the impact of viewing an image of a monkey or prosimian in an anthropomorphic or naturalistic setting, either in contact with or in the absence of a human. Viewing the primate in an anthropomorphic setting while in contact with a person significantly increased their desirability as a pet, which also correlated with increased likelihood of believing the animal was not endangered. The majority of viewers felt that the primates in all tested images were "nervous." When shown in contact with a human, viewers felt they were "sad" and "scared", while also being less "funny." Our findings highlight the potential broader implications of the use of non-human primate performers by the entertainment industry.

  19. Distinct Expression Patterns Of Causative Genes Responsible For Hereditary Progressive Hearing Loss In Non-Human Primate Cochlea.

    PubMed

    Hosoya, Makoto; Fujioka, Masato; Ogawa, Kaoru; Okano, Hideyuki

    2016-02-26

    Hearing impairment is the most frequent sensory deficit in humans. Deafness genes, which harbor pathogenic mutations that have been identified in families with hereditary hearing loss, are commonly expressed in the auditory end organ or the cochlea and may contribute to normal hearing function, yet some of the mouse models carrying these mutations fail to recapitulate the hearing loss phenotype. In this study, we find that distinct expression patterns of those deafness genes in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). We examined 20 genes whose expression in the cochlea has already been reported. The deafness genes GJB3, CRYM, GRHL2, DFNA5, and ATP6B1 were expressed in marmoset cochleae in patterns different from those in mouse cochleae. Of note, all those genes are causative for progressive hearing loss in humans, but not in mice. The other tested genes, including the deafness gene COCH, in which mutation recapitulates deafness in mice, were expressed in a similar manner in both species. The result suggests that the discrepancy in the expression between rodents and primates may account for the phenotypic difference. This limitation of the rodent models can be bypassed by using non-human primate models such as the marmoset.

  20. Distinct Expression Patterns Of Causative Genes Responsible For Hereditary Progressive Hearing Loss In Non-Human Primate Cochlea

    PubMed Central

    Hosoya, Makoto; Fujioka, Masato; Ogawa, Kaoru; Okano, Hideyuki

    2016-01-01

    Hearing impairment is the most frequent sensory deficit in humans. Deafness genes, which harbor pathogenic mutations that have been identified in families with hereditary hearing loss, are commonly expressed in the auditory end organ or the cochlea and may contribute to normal hearing function, yet some of the mouse models carrying these mutations fail to recapitulate the hearing loss phenotype. In this study, we find that distinct expression patterns of those deafness genes in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). We examined 20 genes whose expression in the cochlea has already been reported. The deafness genes GJB3, CRYM, GRHL2, DFNA5, and ATP6B1 were expressed in marmoset cochleae in patterns different from those in mouse cochleae. Of note, all those genes are causative for progressive hearing loss in humans, but not in mice. The other tested genes, including the deafness gene COCH, in which mutation recapitulates deafness in mice, were expressed in a similar manner in both species. The result suggests that the discrepancy in the expression between rodents and primates may account for the phenotypic difference. This limitation of the rodent models can be bypassed by using non-human primate models such as the marmoset. PMID:26915689

  1. Human and Non-Human Primate Genomes Share Hotspots of Positive Selection

    PubMed Central

    Enard, David; Depaulis, Frantz; Roest Crollius, Hugues

    2010-01-01

    Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs) in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution. PMID:20140238

  2. The serial organisation of behaviour by non-human primates; an evaluation of experimental paradigms.

    PubMed

    De Lillio, C

    1996-11-01

    On close examination of research programs which focus, either implicitly or explicitly, on the problem of the organisation of serial order in non-human primates, it is possible to detect some limitations in the paradigms conventionally used. Serial learning studies, which focus on the acquisition of arbitrary lists of unconnected elements point towards a distinction between the representation of ordered series formed by monkeys and pigeons. However, the use of unconnected items prevents an assay of the degree to which primates might be able to impose a structure over the list to be reported. The study of transitive reasoning has been implemented by means of a paradigm where the order of a series is conveyed be presenting a common item in pairs of binary discriminations. Animals tested with this paradigm develop control strategies using more information than that provided by reward contingencies alone. A restriction of this paradigm is that, in its binary form, it does not allow a differentiation between the performance of monkeys and pigeons and even simple models account for a transitive bias in the task. On the basis of these observations it is proposed that novel paradigms which go beyond the binary context, feature multiple connected items, and accord a high degree of spontaneity to the subjects might allow better than traditional ones to uncover qualitative different ways in which different organisms serially organise their behaviour. Some recent research programs based on such rationale, and implemented as search tasks, are then outlined and compared with other approaches to the study of search behaviour. Preliminary results obtained from these studies indicate that the spontaneous serial organisation of multiple connected items might uncover new dimensions of promising comparative relevance.

  3. Data-driven model comparing the effects of glial scarring and interface interactions on chronic neural recordings in non-human primates

    NASA Astrophysics Data System (ADS)

    Malaga, Karlo A.; Schroeder, Karen E.; Patel, Paras R.; Irwin, Zachary T.; Thompson, David E.; Bentley, J. Nicole; Lempka, Scott F.; Chestek, Cynthia A.; Patil, Parag G.

    2016-02-01

    Objective. We characterized electrode stability over twelve weeks of impedance and neural recording data from four chronically-implanted Utah arrays in two rhesus macaques, and investigated the effects of glial scarring and interface interactions at the electrode recording site on signal quality using a computational model. Approach. A finite-element model of a Utah array microelectrode in neural tissue was coupled with a multi-compartmental model of a neuron to quantify the effects of encapsulation thickness, encapsulation resistivity, and interface resistivity on electrode impedance and waveform amplitude. The coupled model was then reconciled with the in vivo data. Histology was obtained seventeen weeks post-implantation to measure gliosis. Main results. From week 1-3, mean impedance and amplitude increased at rates of 115.8 kΩ/week and 23.1 μV/week, respectively. This initial ramp up in impedance and amplitude was observed across all arrays, and is consistent with biofouling (increasing interface resistivity) and edema clearing (increasing tissue resistivity), respectively, in the model. Beyond week 3, the trends leveled out. Histology showed that thin scars formed around the electrodes. In the model, scarring could not match the in vivo data. However, a thin interface layer at the electrode tip could. Despite having a large effect on impedance, interface resistivity did not have a noticeable effect on amplitude. Significance. This study suggests that scarring does not cause an electrical problem with regard to signal quality since it does not appear to be the main contributor to increasing impedance or significantly affect amplitude unless it displaces neurons. This, in turn, suggests that neural signals can be obtained reliably despite scarring as long as the recording site has sufficiently low impedance after accumulating a thin layer of biofouling. Therefore, advancements in microelectrode technology may be expedited by focusing on improvements to the

  4. Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Non-Human Primates

    PubMed Central

    Freitas, AM; Samy, KP; Farris, AB; Leopardi, FV; Song, M; Stempora, L; Strobert, EA; Jenkins, JA; Kirk, AD; Cendales, LC

    2016-01-01

    Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the non-lifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a non-human-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2hi memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model. PMID:26139552

  5. Endocrine-Immune Interactions in Pregnant Non-Human Primates With Intrauterine Infection

    PubMed Central

    Novy, Miles J.

    1997-01-01

    Preterm birth remains the most common cause of perinatal mortality. Although the causes of preterm labor are multifactorial and vary according to gestational age, preterm labor and term labor share common cellular and molecular mechanisms, including stimulation of the fetal hypothalamic-pituitary-adrenal (HPA) axis and endocrine/immune system interactions. We have developed a non-human primate experimental model for intrauterine infection and preterm labor using chronically instrumented rhesus monkeys (Macaca mulatta) with timed gestations. We have documented the temporal and quantitative relationships among intrauterine infection, the synthesis and release of proinflammatory cytokines, prostaglandins, and fetal-placental steroid biosynthesis in this model. Infection-induced preterm parturition is characterized by significant elevations in amniotic fluid proinflammatory cytokines and by increases in fetal adrenal steroid biosynthesis, but not by corresponding increases in placental estrogen biosynthesis characteristic of spontaneous parturition. This suggests that activation of the fetal HPA axis by the stress of infection is accompanied by placental dysfunction and also that infection-induced preterm parturition is not dependent upon the increased estrogen biosynthesis observed in spontaneous parturition. These different endocrine and immune responses have important diagnostic and therapeutic implications in the management of preterm labor. PMID:18476167

  6. Protection of non-human primates against glanders with a gold nanoparticle glycoconjugate vaccine.

    PubMed

    Torres, Alfredo G; Gregory, Anthony E; Hatcher, Christopher L; Vinet-Oliphant, Heather; Morici, Lisa A; Titball, Richard W; Roy, Chad J

    2015-01-29

    The Gram-negative Burkholderia mallei is a zoonotic pathogen and the causative agent of glanders disease. Because the bacteria maintain the potential to be used as a biothreat agent, vaccine strategies are required for human glanders prophylaxis. A rhesus macaque (Macaca mulatta) model of pneumonic (inhalational) glanders was established and the protective properties of a nanoparticle glycoconjugate vaccine composed of Burkholderia thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ∼1×10(4) CFU B. mallei produced mortality in 50% of naïve animals (n=2/4), 2-3 days post-exposure. Although survival benefit was not observed by vaccination with a glycoconjugate glanders vaccine (p=0.42), serum LPS-specific IgG titers were significantly higher on day 80 in 3 vaccinated animals who survived compared with 3 vaccinated animals who died. Furthermore, B. mallei was isolated from multiple organs of both non-vaccinated survivors, but not from any organs of 3 vaccinated survivors at 30 days post-challenge. Taken together, this is the first time a candidate vaccine has been evaluated in a non-human primate aerosol model of glanders and represents the initial step for consideration in pre-clinical studies.

  7. Behavioral, metabolic, and immune consequences of chronic alcohol or cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV model

    PubMed Central

    Molina, Patricia E.; Amedee, Angela M.; Winsauer, Peter; Nelson, Steve; Bagby, Gregory; Simon, Liz

    2015-01-01

    HIV-associated mortality has been significantly reduced with antiretroviral therapy (ART), and HIV infection has become a chronic disease that frequently coexists with many disorders, including substance abuse (Azar et al. 2010; Phillips et al. 2001). Alcohol and drugs of abuse may modify host-pathogen interactions at various levels including behavioral, metabolic, and immune consequences of HIV infection, as well as the ability of the virus to integrate into the genome and replicate in host cells. Identifying mechanisms responsible for these interactions is complicated by many factors, such as the tissue specific responses to viral infection, multiple cellular mechanisms involved in inflammatory responses, neuroendocrine and localized responses to infection, and kinetics of viral replication. An integrated physiological analysis of the biomedical consequences of chronic alcohol and drug use or abuse on disease progression is possible using rhesus macaques infected with simian immunodeficiency virus (SIV), a relevant model of HIV infection. This review will provide an overview of the data gathered using this model to show that chronic administration of two of the most commonly abused substances, alcohol and cannabinoids (Δ9-Tetrahydrocannabinol; THC), affect host-pathogen interactions. PMID:25795088

  8. Molecular phylogeny of anoplocephalid tapeworms (Cestoda: Anoplocephalidae) infecting humans and non-human primates.

    PubMed

    Doležalová, Jana; Vallo, Peter; Petrželková, Klára J; Foitová, Ivona; Nurcahyo, Wisnu; Mudakikwa, Antoine; Hashimoto, Chie; Jirků, Milan; Lukeš, Julius; Scholz, Tomáš; Modrý, David

    2015-09-01

    Anoplocephalid tapeworms of the genus Bertiella Stiles and Hassall, 1902 and Anoplocephala Blanchard, 1848, found in the Asian, African and American non-human primates are presumed to sporadic ape-to-man transmissions. Variable nuclear (5.8S-ITS2; 28S rRNA) and mitochondrial genes (cox1; nad1) of isolates of anoplocephalids originating from different primates (Callicebus oenanthe, Gorilla beringei, Gorilla gorilla, Pan troglodytes and Pongo abelii) and humans from various regions (South America, Africa, South-East Asia) were sequenced. In most analyses, Bertiella formed a monophyletic group within the subfamily Anoplocephalinae, however, the 28S rRNA sequence-based analysis indicated paraphyletic relationship between Bertiella from primates and Australian marsupials and rodents, which should thus be regarded as different taxa. Moreover, isolate determined as Anoplocephala cf. gorillae from mountain gorilla clustered within the Bertiella clade from primates. This either indicates that A. gorillae deserves to be included into the genus Bertiella, or, that an unknown Bertiella species infects also mountain gorillas. The analyses allowed the genetic differentiation of the isolates, albeit with no obvious geographical or host-related patterns. The unexpected genetic diversity of the isolates studied suggests the existence of several Bertiella species in primates and human and calls for revision of the whole group, based both on molecular and morphological data.

  9. A fast multiparameter MRI approach for acute stroke assessment on a 3T clinical scanner: preliminary results in a non-human primate model with transient ischemic occlusion

    PubMed Central

    Tong, Frank; Li, Chun-Xia; Yan, Yumei; Nair, Govind; Nagaoka, Tsukasa; Tanaka, Yoji; Zola, Stuart; Howell, Leonard

    2014-01-01

    Many MRI parameters have been explored and demonstrated the capability or potential to evaluate acute stroke injury, providing anatomical, microstructural, functional, or neurochemical information for diagnostic purposes and therapeutic development. However, the application of multiparameter MRI approach is hindered in clinic due to the very limited time window after stroke insult. Parallel imaging technique can accelerate MRI data acquisition dramatically and has been incorporated in modern clinical scanners and increasingly applied for various diagnostic purposes. In the present study, a fast multiparameter MRI approach including structural T1-weighted imaging (T1W), T2-weighted imaging (T2W), diffusion tensor imaging (DTI), T2-mapping, proton magnetic resonance spectroscopy, cerebral blood flow (CBF), and magnetization transfer (MT) imaging, was implemented and optimized for assessing acute stroke injury on a 3T clinical scanner. A macaque model of transient ischemic stroke induced by a minimal interventional approach was utilized for evaluating the multiparameter MRI approach. The preliminary results indicate the surgical procedure successfully induced ischemic occlusion in the cortex and/or subcortex in adult macaque monkeys (n=4). Application of parallel imaging technique substantially reduced the scanning duration of most MRI data acquisitions, allowing for fast and repeated evaluation of acute stroke injury. Hence, the use of the multiparameter MRI approach with up to five quantitative measures can provide significant advantages in preclinical or clinical studies of stroke disease. PMID:24834423

  10. A Quantitative Proteomic Analysis of Urine from Gamma-Irradiated Non-Human Primates

    PubMed Central

    Byrum, Stephanie D; Burdine, Marie S; Orr, Lisa; Moreland, Linley; Mackintosh, Samuel G; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J

    2016-01-01

    The molecular effects of total body gamma-irradiation exposure are of critical importance as large populations of people could be exposed either by terrorists, nuclear blast, or medical therapy. In this study, we aimed to identify changes in the urine proteome using a non-human primate model system, Rhesus macaque, in order to characterize effects of acute radiation syndrome following whole body irradiation (Co-60) at 6.7 Gy and 7.4 Gy with a twelve day observation period. The urine proteome is potentially a valuable and non-invasive diagnostic for radiation exposure. Using high-resolution mass spectrometry, we identified 2346 proteins in the urine proteome. We show proteins involved in disease, cell adhesion, and metabolic pathway were significantly changed upon exposure to differing levels and durations of radiation exposure. Cell damage increased at a faster rate at 7.4 Gy compared with 6.7 Gy exposures. We report sets of proteins that are putative biomarkers of time- and dose-dependent radiation exposure. The proteomic study presented here is a comprehensive analysis of the urine proteome following radiation exposure. PMID:26962295

  11. Consequences of early adverse rearing experience (EARE) on development: insights from non-human primate studies

    PubMed Central

    Zhang, Bo

    2017-01-01

    Early rearing experiences are important in one's whole life, whereas early adverse rearing experience (EARE) is usually related to various physical and mental disorders in later life. Although there were many studies on human and animals, regarding the effect of EARE on brain development, neuroendocrine systems, as well as the consequential mental disorders and behavioral abnormalities, the underlying mechanisms remain unclear. Due to the close genetic relationship and similarity in social organizations with humans, non-human primate (NHP) studies were performed for over 60 years. Various EARE models were developed to disrupt the early normal interactions between infants and mothers or peers. Those studies provided important insights of EARE induced effects on the physiological and behavioral systems of NHPs across life span, such as social behaviors (including disturbance behavior, social deficiency, sexual behavior, etc), learning and memory ability, brain structural and functional developments (including influences on neurons and glia cells, neuroendocrine systems, e.g., hypothalamic-pituitary-adrenal (HPA) axis, etc). In this review, the effects of EARE and the underlying epigenetic mechanisms were comprehensively summarized and the possibility of rehabilitation was discussed. PMID:28271667

  12. From Sweeping to the Caress: Similarities and Discrepancies between Human and Non-Human Primates' Pleasant Touch.

    PubMed

    Grandi, Laura C

    2016-01-01

    Affective touch plays a key role in affiliative behavior, offering a mechanism for the formation and maintenance of social bonds among conspecifics, both in humans and non-human primates. Furthermore, it has been speculated that the CT fiber system is a specific coding channel for affiliative touch that occurs during skin-to-skin interactions with conspecifics. In humans, this touch is commonly referred to as the caress, and its correlation with the CT fiber system has been widely demonstrated. It has been hypothesized that the sweeping touch that occurs during grooming in non-human primates may modulate the CT fibers, with recent preliminary studies on rhesus monkeys supporting this hypothesis. The present mini-review proposes a comparison between the pleasant touch, caress and sweeping of humans and non-human primates, respectively. The currently available data was therefore reviewed regarding (i) the correlation between pleasant touch and CT fibers both in humans and non-human primates, (ii) the autonomic effects, (iii) the encoding at the central nervous system, (iv) the development from early life to adulthood, and (v) the potential applications of pleasant touch in the daily lives of both humans and non-human primates. Moreover, by considering both the similarities and discrepancies between the human caress and non-human primate sweeping, a possible evolutionary mechanism can be proposed that has developed from sweeping as a utilitarian action with affiliative meaning among monkeys, to the caress as a purely affective gesture associated with humans.

  13. Application of the genome editing tool CRISPR/Cas9 in non-human primates

    PubMed Central

    LUO, Xin; LI, Min; SU, Bing

    2016-01-01

    In the past three years, RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system has been used to facilitate efficient genome editing in many model and non-model animals. However, its application in nonhuman primates is still at the early stage, though in view of the similarities in anatomy, physiology, behavior and genetics, closely related nonhuman primates serve as optimal models for human biology and disease studies. In this review, we summarize the current proceedings of gene editing using CRISPR/Cas9 in nonhuman primates. PMID:27469252

  14. Simultaneous transcranial magnetic stimulation and single neuron recording in alert non-human primates

    PubMed Central

    Mueller, Jerel K.; Grigsby, Erinn M.; Prevosto, Vincent; Petraglia, Frank W.; Rao, Hrishikesh; Deng, Zhi-De; Peterchev, Angel V.; Sommer, Marc A.; Egner, Tobias; Platt, Michael L.; Grill, Warren M.

    2014-01-01

    Transcranial magnetic stimulation (TMS) is a widely used, noninvasive method for stimulating nervous tissue, yet its mechanisms of effect are poorly understood. Here we report novel methods for studying the influence of TMS on single neurons in the brain of alert non-human primates. We designed a TMS coil that focuses its effect near the tip of a recording electrode and recording electronics that enable direct acquisition of neuronal signals at the site of peak stimulus strength minimally perturbed by stimulation artifact in intact, awake monkeys (Macaca mulatta). We recorded action potentials within ~1 ms after 0.4 ms TMS pulses and observed changes in activity that differed significantly for active stimulation as compared to sham stimulation. The methodology is compatible with standard equipment in primate laboratories, allowing for easy implementation. Application of these new tools will facilitate the refinement of next generation TMS devices, experiments, and treatment protocols. PMID:24974797

  15. Daily feeding rhythm in proboscis monkeys: a preliminary comparison with other non-human primates.

    PubMed

    Matsuda, Ikki; Akiyama, Yoshihiro; Tuuga, Augustine; Bernard, Henry; Clauss, Marcus

    2014-04-01

    In non-human primates, the daily feeding rhythm, i.e., temporal fluctuation in feeding activity across the day, has been described but has rarely received much analytical interpretation, though it may play a crucial part in understanding the adaptive significance of primate foraging strategies. This study is the first to describe the detailed daily feeding rhythm in proboscis monkeys (Nasalis larvatus) based on data collected from both riverbank and inland habitats. From May 2005 to May 2006, data on feeding behavior in a group of proboscis monkeys consisting of an alpha-male, six adult females and immatures was collected via continuous focal animal sampling technique in a forest along the Menanggul River, Sabah, Malaysia. In both the male and females, the highest peak of feeding activity was in the late afternoon at 15:00-17:00, i.e., shortly before sleeping. The differences in the feeding rhythm among the seasons appeared to reflect the time spent eating fruit and/or the availability of fruit; clearer feeding peaks were detected when the monkeys spent a relevant amount of time eating fruit, but no clear peak was detected when fruit eating was less frequent. The daily feeding rhythm was not strongly influenced by daily temperature fluctuations. When comparing the daily feeding rhythm of proboscis monkeys to that of other primates, one of the most common temporal patterns detected across primates was a feeding peak in the late afternoon, although it was impossible to demonstrate this statistically because of methodological differences among studies.

  16. Preventive immunization of aged and juvenile non-human primates to beta-amyloid

    PubMed Central

    2012-01-01

    Background Immunization against beta-amyloid (Aβ) is a promising approach for the treatment of Alzheimer’s disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu. Methods Ten non-human primates (NHP) of advanced age (18–26 years) and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [11C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals. Results All juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [11C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P < 0.01). No differences were seen in microglial density or expression of classical and alternative microglial activation markers between immunized and control

  17. Promoting Cas9 degradation reduces mosaic mutations in non-human primate embryos

    PubMed Central

    Tu, Zhuchi; Yang, Weili; Yan, Sen; Yin, An; Gao, Jinquan; Liu, Xudong; Zheng, Yinghui; Zheng, Jiezhao; Li, Zhujun; Yang, Su; Li, Shihua; Guo, Xiangyu; Li, Xiao-Jiang

    2017-01-01

    CRISPR-Cas9 is a powerful new tool for genome editing, but this technique creates mosaic mutations that affect the efficiency and precision of its ability to edit the genome. Reducing mosaic mutations is particularly important for gene therapy and precision genome editing. Although the mechanisms underlying the CRSIPR/Cas9-mediated mosaic mutations remain elusive, the prolonged expression and activity of Cas9 in embryos could contribute to mosaicism in DNA mutations. Here we report that tagging Cas9 with ubiquitin-proteasomal degradation signals can facilitate the degradation of Cas9 in non-human primate embryos. Using embryo-splitting approach, we found that shortening the half-life of Cas9 in fertilized zygotes reduces mosaic mutations and increases its ability to modify genomes in non-human primate embryos. Also, injection of modified Cas9 in one-cell embryos leads to live monkeys with the targeted gene modifications. Our findings suggest that modifying Cas9 activity can be an effective strategy to enhance precision genome editing. PMID:28155910

  18. A wireless transmission neural interface system for unconstrained non-human primates

    NASA Astrophysics Data System (ADS)

    Fernandez-Leon, Jose A.; Parajuli, Arun; Franklin, Robert; Sorenson, Michael; Felleman, Daniel J.; Hansen, Bryan J.; Hu, Ming; Dragoi, Valentin

    2015-10-01

    Objective. Studying the brain in large animal models in a restrained laboratory rig severely limits our capacity to examine brain circuits in experimental and clinical applications. Approach. To overcome these limitations, we developed a high-fidelity 96-channel wireless system to record extracellular spikes and local field potentials from the neocortex. A removable, external case of the wireless device is attached to a titanium pedestal placed in the animal skull. Broadband neural signals are amplified, multiplexed, and continuously transmitted as TCP/IP data at a sustained rate of 24 Mbps. A Xilinx Spartan 6 FPGA assembles the digital signals into serial data frames for transmission at 20 kHz though an 802.11n wireless data link on a frequency-shift key-modulated signal at 5.7-5.8 GHz to a receiver up to 10 m away. The system is powered by two CR123A, 3 V batteries for 2 h of operation. Main results. We implanted a multi-electrode array in visual area V4 of one anesthetized monkey (Macaca fascicularis) and in the dorsolateral prefrontal cortex (dlPFC) of a freely moving monkey (Macaca mulatta). The implanted recording arrays were electrically stable and delivered broadband neural data over a year of testing. For the first time, we compared dlPFC neuronal responses to the same set of stimuli (food reward) in restrained and freely moving conditions. Although we did not find differences in neuronal responses as a function of reward type in the restrained and unrestrained conditions, there were significant differences in correlated activity. This demonstrates that measuring neural responses in freely moving animals can capture phenomena that are absent in the traditional head-fixed paradigm. Significance. We implemented a wireless neural interface for multi-electrode recordings in freely moving non-human primates, which can potentially move systems neuroscience to a new direction by allowing one to record neural signals while animals interact with their environment.

  19. Multisensory Integration in Non-Human Primates during a Sensory-Motor Task.

    PubMed

    Lanz, Florian; Moret, Véronique; Rouiller, Eric Michel; Loquet, Gérard

    2013-01-01

    Daily our central nervous system receives inputs via several sensory modalities, processes them and integrates information in order to produce a suitable behavior. The amazing part is that such a multisensory integration brings all information into a unified percept. An approach to start investigating this property is to show that perception is better and faster when multimodal stimuli are used as compared to unimodal stimuli. This forms the first part of the present study conducted in a non-human primate's model (n = 2) engaged in a detection sensory-motor task where visual and auditory stimuli were displayed individually or simultaneously. The measured parameters were the reaction time (RT) between stimulus and onset of arm movement, successes and errors percentages, as well as the evolution as a function of time of these parameters with training. As expected, RTs were shorter when the subjects were exposed to combined stimuli. The gains for both subjects were around 20 and 40 ms, as compared with the auditory and visual stimulus alone, respectively. Moreover the number of correct responses increased in response to bimodal stimuli. We interpreted such multisensory advantage through redundant signal effect which decreases perceptual ambiguity, increases speed of stimulus detection, and improves performance accuracy. The second part of the study presents single-unit recordings derived from the premotor cortex (PM) of the same subjects during the sensory-motor task. Response patterns to sensory/multisensory stimulation are documented and specific type proportions are reported. Characterization of bimodal neurons indicates a mechanism of audio-visual integration possibly through a decrease of inhibition. Nevertheless the neural processing leading to faster motor response from PM as a polysensory association cortical area remains still unclear.

  20. Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates.

    PubMed

    Elsworth, John D; Jentsch, J David; Vandevoort, Catherine A; Roth, Robert H; Redmond, D Eugene; Leranth, Csaba

    2013-03-01

    Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14-18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA.

  1. Neurochemistry Study of Spinal Cord in Non-Human Primate (Sapajus Spp.)

    PubMed Central

    Torres-da-Silva, K.R.; da Silva, A.V.; Barioni, N.O.; Tessarin, G.W.L.; de Oliveira, J.A.; Ervolino, E.; Horta-Júnior, J.A.C.; Casatti, C.A.

    2016-01-01

    The spinal cord is involved in local, ascending and descending neural pathways. Few studies analyzed the distribution of neuromediators in the laminae of non-human primates along all segments. The present study described the classic neuromediators in the spinal cord of the non-human primate Sapajus spp. through histochemical and immunohistochemical methods. Nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) method showed neuronal somata in the intermediolateral column (IML), central cervical nucleus (CCN), laminae I, II, III, IV, V, VI, VII, VIII and X, besides dense presence of nerve fibers in laminae II and IX. Acetylcholinesterase (AChE) activity was evident in the neuronal somata in laminae V, VI, VII, VIII, IX, CCN, IML and in the Clarke’s column (CC). Immunohistochemistry data revealed neuronal nitric oxide synthase (nNOS) immunoreactivity in neuronal somata and in fibers of laminae I, II, III, VII, VIII, X and IML; choline acetyltransferase (ChAT) in neuronal somata and in fibers of laminae VII, VIII and IX; calcitonin gene-related peptide (CGRP) was noticed in neuronal somata of lamina IX and in nerve fibers of laminae I, II, III, IV, V, VI and VII; substance P (SP) in nerve fibers of laminae I, II, III, IV, V, VI, VII, VIII, IX, X, CCN, CC and IML; serotonin (5-HT) and vesicular glutamate transporter-1 (VGLUT1) was noticed in nerve fibers of all laminae; somatostatin (SOM) in neuronal somata of laminae III, IV, V, VI, VII, VIII and IX and nerve fibers in laminae I, II, V, VI, VII, X and IML; calbindin (Cb) in neuronal somata of laminae I, II, VI, VII, IX and X; parvalbumin (PV) was found in neuronal somata and in nerve fibers of laminae III, IV, V, VI, VII, VIII, IX and CC; finally, gamma-amino butyric acid (GABA) was present in neuronal somata of laminae V, VI, VII, VIII, IX and X. This study revealed interesting results concerning the chemoarchitecture of the Sapajus spp. spinal cord with a distribution pattern mostly similar to

  2. An ethnoprimatological approach to assessing levels of tolerance between human and commensal non-human primates in Sri Lanka.

    PubMed

    Nekaris, Anne-Isola; Boulton, Alex; Nijman, Vincent

    2013-01-01

    Human and non-human primates increasingly are forced to live commensally, and understanding the human-nonhuman interconnections are paramount in understanding tolerance and conflict. In our study area, the heavily deforested parts of southern Sri Lanka humans and primates live side by side and prevalent religious tenets encourage a peaceful co-existence. We quantify the attitudes of rural communities towards three resident primate species (red slender loris, purple-faced langur, toque macaque) and wildlife conservation through semi-structured interviews with 301 people. Presence of the three primates on people' s land or farms was not related to the distance to the nearest forest but for langurs the incidence of crop-raiding was negatively related to distance to the forest. Despite Buddhist' s beliefs about 10% of interviewees indicated having killed primates (in the past) but levels of killing was not related to awareness of protective status of the primates. Overall however positive attitudes towards primates prevailed, without noticeable influence of sex, education or employment type. There was overwhelming support for forest protection measures - not because of the primates but mainly for water preservation and for ensuring a steady timber supply. We found that despite high levels of deforestation, and an increase of encroachment of humans into primate habitats, attitudes has led only to a limited increased level of tension between humans and primates.

  3. Brains, innovations, tools and cultural transmission in birds, non-human primates, and fossil hominins.

    PubMed

    Lefebvre, Louis

    2013-01-01

    Recent work on birds and non-human primates has shown that taxonomic differences in field measures of innovation, tool use and social learning are associated with size of the mammalian cortex and avian mesopallium and nidopallium, as well as ecological traits like colonization success. Here, I review this literature and suggest that many of its findings are relevant to hominin intelligence. In particular, our large brains and increased intelligence may be partly independent of our ape phylogeny and the result of convergent processes similar to those that have molded avian and platyrrhine intelligence. Tool use, innovativeness and cultural transmission might be linked over our past and in our brains as operations of domain-general intelligence. Finally, colonization of new areas may have accompanied increases in both brain size and innovativeness in hominins as they have in other mammals and in birds, potentially accelerating hominin evolution via behavioral drive.

  4. Brains, innovations, tools and cultural transmission in birds, non-human primates, and fossil hominins

    PubMed Central

    Lefebvre, Louis

    2013-01-01

    Recent work on birds and non-human primates has shown that taxonomic differences in field measures of innovation, tool use and social learning are associated with size of the mammalian cortex and avian mesopallium and nidopallium, as well as ecological traits like colonization success. Here, I review this literature and suggest that many of its findings are relevant to hominin intelligence. In particular, our large brains and increased intelligence may be partly independent of our ape phylogeny and the result of convergent processes similar to those that have molded avian and platyrrhine intelligence. Tool use, innovativeness and cultural transmission might be linked over our past and in our brains as operations of domain-general intelligence. Finally, colonization of new areas may have accompanied increases in both brain size and innovativeness in hominins as they have in other mammals and in birds, potentially accelerating hominin evolution via behavioral drive. PMID:23761751

  5. Alternative methods for the use of non-human primates in biomedical research.

    PubMed

    Burm, Saskia M; Prins, Jan-Bas; Langermans, Jan; Bajramovic, Jeffrey J

    2014-01-01

    The experimental use of non-human primates (NHP) in Europe is tightly regulated and is only permitted when there are no alternatives available. As a result, NHP are most often used in late, pre-clinical phases of biomedical research. Although the impetus for scientists, politicians and the general public to replace, reduce and refine NHP in biomedical research is strong, the development of 3Rs technology for NHP poses specific challenges. In February 2014 a workshop on "Alternative methods for the use of NHP in biomedical research" was organized within the international exchange program of EUPRIM-Net II, a European infrastructure initiative that links biomedical primate research centers. The workshop included lectures by key scientists in the field of alternatives as well as by experts from governmental and non-governmental organizations. Furthermore, parallel sessions were organized to stimulate discussion on the challenges of advancing the use of alternative methods for NHP. Subgroups voted on four statements and together composed a list with opportunities and priorities. This report summarizes the presentations that were held, the content of the discussion sessions and concludes with recommendations on 3Rs development for NHP specifically. These include technical, conceptual as well as political topics.

  6. Mosquitoes as Potential Bridge Vectors of Malaria Parasites from Non-Human Primates to Humans

    PubMed Central

    Verhulst, Niels O.; Smallegange, Renate C.; Takken, Willem

    2012-01-01

    Malaria is caused by Plasmodium parasites which are transmitted by mosquitoes. Until recently, human malaria was considered to be caused by human-specific Plasmodium species. Studies on Plasmodium parasites in non-human primates (NHPs), however, have identified parasite species in gorillas and chimpanzees that are closely related to human Plasmodium species. Moreover, P. knowlesi, long known as a parasite of monkeys, frequently infects humans. The requirements for such a cross-species exchange and especially the role of mosquitoes in this process are discussed, as the latter may act as bridge vectors of Plasmodium species between different primates. Little is known about the mosquito species that would bite both humans and NHPs and if so, whether humans and NHPs share the same Plasmodium vectors. To understand the vector-host interactions that can lead to an increased Plasmodium transmission between species, studies are required that reveal the nature of these interactions. Studying the potential role of NHPs as a Plasmodium reservoir for humans will contribute to the ongoing efforts of human malaria elimination, and will help to focus on critical areas that should be considered in achieving this goal. PMID:22701434

  7. Total Body Irradiation in the "Hematopoietic" Dose Range Induces Substantial Intestinal Injury in Non-Human Primates.

    PubMed

    Wang, Junru; Shao, Lijian; Hendrickson, Howard P; Liu, Liya; Chang, Jianhui; Luo, Yi; Seng, John; Pouliot, Mylene; Authier, Simon; Zhou, Daohong; Allaben, William; Hauer-Jensen, Martin

    2015-11-01

    The non-human primate has been a useful model for studies of human acute radiation syndrome (ARS). However, to date structural changes in various parts of the intestine after total body irradiation (TBI) have not been systematically studied in this model. Here we report on our current study of TBI-induced intestinal structural injury in the non-human primate after doses typically associated with hematopoietic ARS. Twenty-four non-human primates were divided into three groups: sham-irradiated control group; and total body cobalt-60 (60Co) 6.7 Gy gamma-irradiated group; and total body 60Co 7.4 Gy gamma-irradiated group. After animals were euthanized at day 4, 7 and 12 postirradiation, sections of small intestine (duodenum, proximal jejunum, distal jejunum and ileum) were collected and fixed in 10% formalin. The intestinal mucosal surface length, villus height and crypt depths were assessed by computer-assisted image analysis. Plasma citrulline levels were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total bone marrow cells were counted and hematopoietic stem/progenitor cells in bone marrow were analyzed by flow cytometer. Histopathologically, all segments exhibited conspicuous disappearance of plicae circulares and prominent atrophy of crypts and villi. Intestinal mucosal surface length was significantly decreased in all intestinal segments on day 4, 7 and 12 after irradiation (P < 0.02-P < 0.001). Villus height was significantly reduced in all segments on day 4 and 7 (P = 0.02-0.005), whereas it had recovered by day 12 (P > 0.05). Crypt depth was also significantly reduced in all segments on day 4, 7 and 12 after irradiation (P < 0.04-P < 0.001). Plasma citrulline levels were dramatically reduced after irradiation, consistent with intestinal mucosal injury. Both 6.7 and 7.4 Gy TBI reduced total number of bone marrow cells. And further analysis showed that the number and function of CD45(+)CD34(+) hematopoietic stem/progenitors in bone

  8. Absence of mutations associated with sulfa resistance in Pneumocystis carinii dihydropteroate synthase gene from non-human primates.

    PubMed

    Demanche, C; Guillot, J; Berthelemy, M; Petitt, T; Roux, P; Wakefield, A E

    2002-06-01

    The dihydropteroate synthase (DHPS) gene from Pneumocystis carinii isolated from non-human primates was amplified using a polymerase chain reaction (PCR) and sequenced to analyse point mutations associated with sulfa resistance. P. carinii DHPS gene amplification was obtained from eight lung samples from five New World primate species and one Old World primate species. None of the animals had been exposed to sulfa drugs and only the wild-type P. carinii DHPS sequence at codons 55 and 57 was observed. These data support the hypothesis that high rates of DHPS mutants in P. carinii f. sp. hominis have arisen with increased use of sulfa drugs for P. carinii pneumonia prophylaxis.

  9. Longitudinal Characterization of Escherichia coli in Healthy Captive Non-Human Primates

    PubMed Central

    Clayton, Jonathan B.; Danzeisen, Jessica L.; Trent, Ava M.; Murphy, Tami; Johnson, Timothy J.

    2014-01-01

    The gastrointestinal (GI) tracts of non-human primates (NHPs) are well known to harbor Escherichia coli, a known commensal of human beings and animals. While E. coli is a normal inhabitant of the mammalian gut, it also exists in a number of pathogenic forms or pathotypes, including those with predisposition for the GI tract as well as the urogenital tract. Diarrhea in captive NHPs has long been a problem in both zoo settings and research colonies, including the Como Zoo. It is an animal welfare concern, as well as a public health concern. E. coli has not been extensively studied; therefore, a study was performed during the summer of 2009 in collaboration with a zoo in Saint Paul, MN, which was previously experiencing an increased incidence and severity of diarrhea among their NHP collection. Fresh fecal samples were collected weekly from each member of the primate collection, between June and August of 2009, and E. coli were isolated. A total of 33 individuals were included in the study, representing eight species. E. coli isolates were examined for their genetic relatedness, phylogenetic relationships, plasmid replicon types, virulence gene profiles, and antimicrobial susceptibility profiles. A number of isolates were identified containing virulence genes commonly found in several different E. coli pathotypes, and there was evidence of clonal transmission of isolates between animals and over time. Overall, the manifestation of chronic diarrhea in the Como Zoo primate collection is a complex problem whose solution will require regular screening for microbial agents and consideration of environmental causes. This study provides some insight toward the sharing of enteric bacteria between such animals. PMID:26664923

  10. The neural bases of crossmodal object recognition in non-human primates and rodents: a review.

    PubMed

    Cloke, Jacob M; Jacklin, Derek L; Winters, Boyer D

    2015-05-15

    The ability to integrate information from different sensory modalities to form unique multisensory object representations is a highly adaptive cognitive function. Surprisingly, non-human animal studies of the neural substrates of this form of multisensory integration have been somewhat sparse until very recently, and this may be due in part to a relative paucity of viable testing methods. Here we review the historical development and use of various "crossmodal" cognition tasks for non-human primates and rodents, focusing on tests of "crossmodal object recognition", the ability to recognize an object across sensory modalities. Such procedures have great potential to elucidate the cognitive and neural bases of object representation as it pertains to perception and memory. Indeed, these studies have revealed roles in crossmodal cognition for various brain regions (e.g., prefrontal and temporal cortices) and neurochemical systems (e.g., acetylcholine). A recent increase in behavioral and physiological studies of crossmodal cognition in rodents augurs well for the future of this research area, which should provide essential information about the basic mechanisms of object representation in the brain, in addition to fostering a better understanding of the causes of, and potential treatments for, cognitive deficits in human diseases characterized by atypical multisensory integration.

  11. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates

    NASA Astrophysics Data System (ADS)

    Veiseh, Omid; Doloff, Joshua C.; Ma, Minglin; Vegas, Arturo J.; Tam, Hok Hei; Bader, Andrew R.; Li, Jie; Langan, Erin; Wyckoff, Jeffrey; Loo, Whitney S.; Jhunjhunwala, Siddharth; Chiu, Alan; Siebert, Sean; Tang, Katherine; Hollister-Lock, Jennifer; Aresta-Dasilva, Stephanie; Bochenek, Matthew; Mendoza-Elias, Joshua; Wang, Yong; Qi, Merigeng; Lavin, Danya M.; Chen, Michael; Dholakia, Nimit; Thakrar, Raj; Lacík, Igor; Weir, Gordon C.; Oberholzer, Jose; Greiner, Dale L.; Langer, Robert; Anderson, Daniel G.

    2015-06-01

    The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions.

  12. A multi-site array for combined local electrochemistry and electrophysiology in the non-human primate brain

    PubMed Central

    Disney, Anita A; McKinney, Collin; Grissom, Larry; Lu, Xuekun; Reynolds, John H

    2015-01-01

    Background Currently, the primary technique employed in circuit-level study of the brain is electrophysiology, recording local field or action potentials (LFPs or APs). However most communication between neurons is chemical and the relationship between electrical activity within neurons and chemical signaling between them is not well understood in vivo, particularly for molecules that signal at least in part by non-synaptic transmission. New Method We describe a multi-contact array and accompanying head stage circuit that together enable concurrent electrophysiological and electrochemical recording. The array is small (<200μm) and can be assembled into a device of arbitrary length. It is therefore well-suited for use in all major in vivo model systems in neuroscience, including non-human primates where the large brain and need for daily insertion and removal of recording devices places particularly strict demands on design. Results We present a protocol for array fabrication. We then show that a device built in the manner described can record LFPs and perform enzyme-based amperometric detection of choline in the awake macaque monkey. Comparison with existing methods Existing methods allow single mode (electrophysiology or electrochemistry) recording. This system is designed for concurrent, dual-mode recording. It is also the only system designed explicitly to meet the challenges of recording in non-human primates. Conclusions Our system offers the possibility for conducting in vivo studies in a range of species that examine the relationship between the electrical activity of neurons and their chemical environment, with exquisite spatial and temporal precision. PMID:26226654

  13. [Ethical and legal aspects of animal experiments on non-human primates].

    PubMed

    Luy, J

    2007-03-01

    Animal experiments on non-human primates give cause for ethical concerns for three reasons (1) the inclusion of "ethical animal protection" in the German Constitution (Article 20a of the "Grundgesetz" GG, 2002) has led to real consequences for the application process with respect to the use of primates for fundamental research; (2) the legal requirements in Europe to ensure animal welfare are currently being tightened and (3) the global problem of the protection of species, especially with respect to the capturing and subsequent sale of primates is still unsolved. As a result of the way humans interpret the term justice (the principle of equality) it was to be expected that great apes, being the animals that most closely resemble humans, would play a key role in the establishment of animal protection laws. In 1997,Great Britain and Ireland made it illegal to conduct experiments on great apes. In 1999, New Zealand went even further and created a kind of basic rights for great apes. In 2003,The Netherlands forbade animal experiments using great apes as did Sweden, which also included gibbons in this ban (which is in line with current taxonomy, which considers gibbons to belong to the family Hominidae). In 2006 Austria forbade experiments carried out on chimpanzees, bonobos, gorillas, orang-utans, and gibbons. Only recently, a state commission on ethics in Switzerland demanded that the Swiss government do the same. And the summer of 2006 saw a debate in Spain on the inclusion of the protection of great apes in the primary goals of the state. Due to the principle of equality, a further extension (both geographically and systemically) of the exclusion of great apes from animal experiments is to be expected. Since Article 20a GG on "ethical animal protection" came into effect on August 1,2002, the regulatory authorities in Germany have the right to independently check and control animal experiments as to their ethical tenability (Administrative Court Giessen, confirmed

  14. Simian foamy virus in non-human primates and cross-species transmission to humans in Gabon: an emerging zoonotic disease in central Africa?

    PubMed

    Mouinga-Ondémé, Augustin; Kazanji, Mirdad

    2013-06-19

    It is now known that all human retroviruses have a non-human primate counterpart. It has been reported that the presence of these retroviruses in humans is the result of interspecies transmission. Several authors have described the passage of a simian retrovirus, simian foamy virus (SFV), from primates to humans. To better understand this retroviral "zoonosis" in natural settings, we evaluated the presence of SFV in both captive and wild non-human primates and in humans at high risk, such as hunters and people bitten by a non-human primate, in Gabon, central Africa. A high prevalence of SFV was found in blood samples from non-human primates and in bush meat collected across the country. Mandrills were found to be highly infected with two distinct strains of SFV, depending on their geographical location. Furthermore, samples collected from hunters and non-human primate laboratory workers showed clear, extensive cross-species transmission of SFV. People who had been bitten by mandrills, gorillas and chimpanzees had persistent SFV infection with low genetic drift. Thus, SFV is presumed to be transmitted from non-human primates mainly through severe bites, involving contact between infected saliva and blood. In this review, we summarize and discuss our five-year observations on the prevalence and dissemination of SFV in humans and non-human primates in Gabon.

  15. Do non-human primates cooperate? Evidences of motor coordination during a joint action task in macaque monkeys.

    PubMed

    Visco-Comandini, Federica; Ferrari-Toniolo, Simone; Satta, Eleonora; Papazachariadis, Odysseas; Gupta, Rajnish; Nalbant, Laura Elena; Battaglia-Mayer, Alexandra

    2015-09-01

    Humans are intensively social primates, therefore many of their actions are dedicated to communication and interaction with other individuals. Despite the progress in understanding the cognitive and neural processes that allow humans to perform cooperative actions, in non-human primates only few studies have investigated the ability to interact with a partner in order to reach a common goal. These studies have shown that in naturalistic conditions animals engage in various types of social behavior that involve forms of mutual coordination and cooperation. However, little is known on the capacity of non-human primates to actively cooperate in a controlled experimental setting, which allows full characterization of the motor parameters underlying individual action and their change during motor cooperation. To this aim, we analyzed the behavior of three pairs of macaque monkeys trained to perform solo and joint-actions by exerting a force on an isometric joystick, as to move an individual or a common cursor toward visual targets on a screen. We found that during cooperation monkeys reciprocally adapt their behavior by changing the parameters that define the spatial and temporal aspects of their action, as to fine tune their joint effort, and maximize their common performance. Furthermore the results suggest that when acting together the movement parameters that specify each actor's behavior are not only modulated during execution, but also during planning. These findings provide the first quantitative description of action coordination in non-human primates during the performance of a joint action task.

  16. A Microneedle Patch Containing Measles Vaccine is Immunogenic in Non-human Primates

    PubMed Central

    Edens, Chris; Collins, Marcus L.; Goodson, James L.; Rota, Paul A.; Prausnitz, Mark R.

    2015-01-01

    Very high vaccination coverage is required to eliminate measles, but achieving high coverage can be constrained by the logistical challenges associated with subcutaneous injection. To simplify logistics of vaccine delivery, a patch containing micron-scale polymeric needles was formulated to encapsulate the standard dose of measles vaccine (1000 TCID50) and the immunogenicity of the microneedle patch was compared with subcutaneous injection in rhesus macaques. The microneedle patch was administered without reconstitution with diluent, dissolved in skin within 10 minutes, and caused only mild, transient skin erythema. Both groups of rhesus macaques generated neutralizing antibody responses to measles that were consistent with protection and the neutralizing antibody titers were equivalent. In addition, the microneedle patches maintained an acceptable level of potency after storage at elevated temperature suggesting improved thermostability compared to standard lyophilized vaccine. In conclusion, a measles microneedle patch vaccine was immunogenic in non-human primates, and this approach offers a promising delivery method that could help increase vaccination coverage. PMID:25770786

  17. Seasonal mortality patterns in non-human primates: implications for variation in selection pressures across environments.

    PubMed

    Gogarten, Jan F; Brown, Leone M; Chapman, Colin A; Cords, Marina; Doran-Sheehy, Diane; Fedigan, Linda M; Grine, Frederick E; Perry, Susan; Pusey, Anne E; Sterck, Elisabeth H M; Wich, Serge A; Wright, Patricia C

    2012-10-01

    Examining seasonal mortality patterns can yield insights into the drivers of mortality and thus potential selection pressures acting on individuals in different environments. We compiled adult and juvenile mortality data from nine wild non-human primate taxa to investigate the role of seasonality in patterns of mortality and address the following questions: Is mortality highly seasonal across species? Does greater environmental seasonality lead to more seasonal mortality patterns? If mortality is seasonal, is it higher during wet seasons or during periods of food scarcity? and Do folivores show less seasonal mortality than frugivores? We found seasonal mortality patterns in five of nine taxa, and mortality was more often tied to wet seasons than food-scarce periods, a relationship that may be driven by disease. Controlling for phylogeny, we found a positive relationship between the degree of environmental seasonality and mortality, with folivores exhibiting more seasonal mortality than frugivores. These results suggest that mortality patterns are influenced both by diet and degree of environmental seasonality. Applied to a wider array of taxa, analyses of seasonal mortality patterns may aid understanding of life-history evolution and selection pressures acting across a broad spectrum of environments and spatial and temporal scales.

  18. SEASONAL MORTALITY PATTERNS IN NON-HUMAN PRIMATES: IMPLICATIONS FOR VARIATION IN SELECTION PRESSURES ACROSS ENVIRONMENTS

    PubMed Central

    Gogarten, Jan F.; Brown, Leone M.; Chapman, Colin A.; Cords, Marina; Doran-Sheehy, Diane; Fedigan, Linda M.; Grine, Frederick E.; Perry, Susan; Pusey, Anne E.; Sterck, Elisabeth H. M.; Wich, Serge A.; Wright, Patricia C.

    2014-01-01

    Examining seasonal mortality patterns can yield insights into the drivers of mortality and thus potential selection pressures acting on individuals in different environments. We compiled adult and juvenile mortality data from nine wild non-human primate taxa to investigate the role of seasonality in patterns of mortality and address the following questions: Is mortality highly seasonal across species? Does greater environmental seasonality lead to more seasonal mortality patterns? If mortality is seasonal, is it higher during wet seasons or during periods of food scarcity? and Do folivores show less seasonal mortality than frugivores? We found seasonal mortality patterns in five of nine taxa, and mortality was more often tied to wet seasons than food-scarce periods, a relationship that may be driven by disease. Controlling for phylogeny, we found a positive relationship between the degree of environmental seasonality and mortality, with folivores exhibiting more seasonal mortality than frugivores. These results suggest that mortality patterns are influenced both by diet and degree of environmental seasonality. Applied to a wider array of taxa, analyses of seasonal mortality patterns may aid understanding of life-history evolution and selection pressures acting across a broad spectrum of environments and spatial and temporal scales. PMID:23025613

  19. Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.

    PubMed

    Verina, Tatyana; Schneider, Jay S; Guilarte, Tomás R

    2013-03-13

    Aggregation of α-synuclein (α-syn) in the brain is a defining pathological feature of neurodegenerative disorders classified as synucleinopathies. They include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism. In this study, we examined α-syn immunoreactivity in the frontal cortex of Cynomolgus macaques as part of a multidisciplinary assessment of the neurological effects produced by exposure to moderate levels of Mn. We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers. Some of these neurons displayed loss of Nissl staining with α-syn-positive spherical aggregates. In the white matter we also observed α-syn-positive glial cells and in some cases α-syn-positive neurites. These findings suggest that Mn exposure promotes α-syn aggregation in neuronal and glial cells that may ultimately lead to degeneration in the frontal cortex gray and white matter. To our knowledge, this is the first report of Mn-induced neuronal and glial cell α-syn accumulation and aggregation in the frontal cortex of non-human primates.

  20. A microneedle patch containing measles vaccine is immunogenic in non-human primates.

    PubMed

    Edens, Chris; Collins, Marcus L; Goodson, James L; Rota, Paul A; Prausnitz, Mark R

    2015-09-08

    Very high vaccination coverage is required to eliminate measles, but achieving high coverage can be constrained by the logistical challenges associated with subcutaneous injection. To simplify the logistics of vaccine delivery, a patch containing micron-scale polymeric needles was formulated to encapsulate the standard dose of measles vaccine (1000 TCID₅₀) and the immunogenicity of the microneedle patch was compared with subcutaneous injection in rhesus macaques. The microneedle patch was administered without reconstitution with diluent, dissolved in skin within 10 min, and caused only mild, transient skin erythema. Both groups of rhesus macaques generated neutralizing antibody responses to measles that were consistent with protection and the neutralizing antibody titers were equivalent. In addition, the microneedle patches maintained an acceptable level of potency after storage at elevated temperature suggesting improved thermostability compared to standard lyophilized vaccine. In conclusion, a measles microneedle patch vaccine was immunogenic in non-human primates, and this approach offers a promising delivery method that could help increase vaccination coverage.

  1. Non-human primates in neuroscience research: The case against its scientific necessity.

    PubMed

    Bailey, Jarrod; Taylor, Kathy

    2016-03-01

    Public opposition to non-human primate (NHP) experiments is significant, yet those who defend them cite minimal harm to NHPs and substantial human benefit. Here we review these claims of benefit, specifically in neuroscience, and show that: a) there is a default assumption of their human relevance and benefit, rather than robust evidence; b) their human relevance and essential contribution and necessity are wholly overstated; c) the contribution and capacity of non-animal investigative methods are greatly understated; and d) confounding issues, such as species differences and the effects of stress and anaesthesia, are usually overlooked. This is the case in NHP research generally, but here we specifically focus on the development and interpretation of functional magnetic resonance imaging (fMRI), deep brain stimulation (DBS), the understanding of neural oscillations and memory, and investigation of the neural control of movement and of vision/binocular rivalry. The increasing power of human-specific methods, including advances in fMRI and invasive techniques such as electrocorticography and single-unit recordings, is discussed. These methods serve to render NHP approaches redundant. We conclude that the defence of NHP use is groundless, and that neuroscience would be more relevant and successful for humans, if it were conducted with a direct human focus. We have confidence in opposing NHP neuroscience, both on scientific as well as on ethical grounds.

  2. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration.

    PubMed

    Freeman, Willard M; Vanguilder, Heather D; Guidone, Elizabeth; Krystal, John H; Grant, Kathleen A; Vrana, Kent E

    2011-08-01

    Objective diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. Two-dimensional difference in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within-subject samples collected before exposure to ethanol and after 3 months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of serum amyloid A4 (SAA4), retinol-binding protein, inter-alpha inhibitor H4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption.

  3. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration

    PubMed Central

    Freeman, Willard M.; VanGuilder, Heather D.; Guidone, Elizabeth; Krystal, John H.; Grant, Kathleen A.; Vrana, Kent E.

    2011-01-01

    Objective diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. 2-dimensional in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within subject samples collected before exposure to ethanol and after three months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of SAA4, RBP, ITIH4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption. PMID:21303580

  4. Isolation of Anti-Ricin Protective Antibodies Exhibiting High Affinity from Immunized Non-Human Primates

    PubMed Central

    Noy-Porat, Tal; Rosenfeld, Ronit; Ariel, Naomi; Epstein, Eyal; Alcalay, Ron; Zvi, Anat; Kronman, Chanoch; Ordentlich, Arie; Mazor, Ohad

    2016-01-01

    Ricin, derived from the castor bean plant Ricinus communis, is one of the most potent and lethal toxins known, against which there is no available antidote. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this study was to isolate high affinity anti-ricin antibodies that possess potent toxin-neutralization capabilities. Two non-human primates were immunized with either a ricin-holotoxin- or subunit-based vaccine, to ensure the elicitation of diverse high affinity antibodies. By using a comprehensive set of primers, immune scFv phage-displayed libraries were constructed and panned. A panel of 10 antibodies (five directed against the A subunit of ricin and five against the B subunit) was isolated and reformatted into a full-length chimeric IgG. All of these antibodies were found to neutralize ricin in vitro, and several conferred full protection to ricin-intoxicated mice when given six hours after exposure. Six antibodies were found to possess exceptionally high affinity toward the toxin, with KD values below pM (koff < 1 × 10−7 s−1) that were well correlated with their ability to neutralize ricin. These antibodies, alone or in combination, could be used for the development of a highly-effective therapeutic preparation for post-exposure treatment of ricin intoxication. PMID:26950154

  5. Blood microsampling from the ear capillary in non-human primates.

    PubMed

    Lefevre, Arthur; Ballesta, Sébastien; Pozzobon, Mathieu; Charieau, Jean-Luc; Duperrier, Sandra; Sirigu, Angela; Duhamel, Jean-René

    2015-10-01

    Blood sampling from awake non-human primates (NHPs) is classically performed under constraint in the cephalic or saphenous vein. It is a challenging, potentially harmful and stressful procedure which may lead to biased results and raises ethical concerns. Laboratory NHPs undergo a head-restrained procedure allowing for a safer procedure of collecting blood from their ears. Using regular capillary blood collection devices 500 µL of blood can be easily withdrawn per puncture point, which is sufficient for performing most of the usual modern biological assays. This procedure has been validated by measuring total proteins, cortisol and vasopressin concentrations from concomitant blood samples taken from the saphenous vein and the ear capillary vessels of macaques (n = 16). We observed strong correlations between the blood concentrations of total proteins, cortisol and vasopressin (r = 0.72, r = 0.63, r = 0.83, respectively; all P values <0.01) taken from the saphenous vein and from the ear capillary. There were no significant differences between blood concentrations taken from the saphenous vein and the ear capillary. Our alternative to the classical blood collection procedure is harmless and can be routinely performed, which can therefore improve scientific results while increasing animal welfare in accordance with the 3R (replacement, reduction and refinement) principles.

  6. Isolation of Anti-Ricin Protective Antibodies Exhibiting High Affinity from Immunized Non-Human Primates.

    PubMed

    Noy-Porat, Tal; Rosenfeld, Ronit; Ariel, Naomi; Epstein, Eyal; Alcalay, Ron; Zvi, Anat; Kronman, Chanoch; Ordentlich, Arie; Mazor, Ohad

    2016-03-03

    Ricin, derived from the castor bean plant Ricinus communis, is one of the most potent and lethal toxins known, against which there is no available antidote. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this study was to isolate high affinity anti-ricin antibodies that possess potent toxin-neutralization capabilities. Two non-human primates were immunized with either a ricin-holotoxin- or subunit-based vaccine, to ensure the elicitation of diverse high affinity antibodies. By using a comprehensive set of primers, immune scFv phage-displayed libraries were constructed and panned. A panel of 10 antibodies (five directed against the A subunit of ricin and five against the B subunit) was isolated and reformatted into a full-length chimeric IgG. All of these antibodies were found to neutralize ricin in vitro, and several conferred full protection to ricin-intoxicated mice when given six hours after exposure. Six antibodies were found to possess exceptionally high affinity toward the toxin, with KD values below pM (k(off )< 1 × 10(-7) s(-1)) that were well correlated with their ability to neutralize ricin. These antibodies, alone or in combination, could be used for the development of a highly-effective therapeutic preparation for post-exposure treatment of ricin intoxication.

  7. Spatial Overlap Between People and Non-human Primates in a Fragmented Landscape.

    PubMed

    Paige, Sarah B; Bleecker, Johanna; Mayer, Jonathan; Goldberg, Tony

    2017-03-01

    In western Uganda, the landscape surrounding Kibale National Park (KNP) contains households, trading centers, roads, fields, and forest fragments. The mosaic arrangement of these landscape features is thought to enhance human-primate interaction, leading to primate population declines and increased bi-directional disease transmission. Using a social-ecological systems research framework that captures the complexity of interaction among people, wildlife, and environment, we studied five forest fragments near KNP and conducted intensive on-the-ground mapping to identify locations of human-primate spatial overlap. Primate locations and human activities were distributed within, on the edges, and far beyond fragment borders. Analysis of shared spaces indicated that 5.5% of human space overlapped with primate spaces, while 69.5% of primate spaces overlapped with human spaces. Nearest neighbor analysis indicated that human activities were significantly spatially clustered within and around individual fragments, as were primate locations. Getis-Ord statistics revealed statistically significant "hotspots" of human activity and primate activity, but only one location where spatial overlap between humans and primates was statistically significant. Human activities associated with collecting fuelwood and other forest products were the primary drivers of human-primate overlap; however, primates also spent time outside of forest fragments in agricultural spaces. These results demonstrate that fragmented landscapes are not uniform with respect to human-primate overlap, and that the implications of human-primate interaction, such as primate population declines and possible cross-species disease transmission, are spatially aggregated.

  8. Preference and consequences: A preliminary look at whether preference impacts oral processing in non-human primates.

    PubMed

    Vinyard, Christopher J; Thompson, Cynthia L; Doherty, Alison; Robl, Nicholas

    2016-09-01

    Non-human primates demonstrate food preferences much like humans. We have little insight, however, into how those preferences impact oral processing in primates. To begin describing this relationship, we conducted a preliminary analysis measuring food preference in two tufted capuchins (Cebus apella) and comparing ranked preference to physiological variables during chewing of these foods. Food preference was assessed for each monkey across 12 foods, including monkey biscuits and 11 foods consumed by humans (e.g., various fruits and nuts). Animals chose from randomized pairs of foods to generate a ranked scale across the 12 foods. Contemporaneous with preference testing, electromyographic (EMG) activity was measured for the jaw-closing muscles to assess oral physiology during chewing of these foods. As expected, these capuchins exhibited clear preferences among these 12 foods. Based on their preferences, we identified sets of preferred and non-preferred brittle (i.e., almond versus monkey chow) and ductile (i.e., dates and prunes versus apricots) foods for physiological comparisons that broadly control variation in food mechanical properties (FMPs). As expected, oral physiology varied with FMPs in each animal. Within brittle and ductile groupings, we observed several significant differences in chewing cycle length and relative muscle activation levels that are likely related to food preference. These differences tended to be complex and individual specific. The two capuchins chewed non-preferred apricots significantly faster than preferred dates and prunes. Effect sizes for preference were smaller than those for FMPs, supporting the previous focus on FMPs in primate dietary research. Although preliminary, these results suggest that food preference may influence oral physiology in non-human primates. The prospect that this relationship exists in monkeys raises the possibility that a link between food preference and oral processing in humans may be based on shared

  9. Consensus-degenerate hybrid oligonucleotide primers (CODEHOPs) for the detection of novel viruses in non-human primates.

    PubMed

    Staheli, Jeannette P; Ryan, Jonathan T; Bruce, A Gregory; Boyce, Richard; Rose, Timothy M

    2009-09-01

    Consensus-degenerate hybrid oligonucleotide primers (CODEHOPs) have proven to be a powerful tool for the identification of novel genes. CODEHOPs are designed from highly-conserved regions of multiply-aligned protein sequences from members of a gene family and are used in PCR amplification to identify distantly-related genes. The CODEHOP approach has been used to identify novel pathogens by targeting amino acid motifs conserved in specific pathogen families. We initiated a program utilizing the CODEHOP approach to develop PCR-based assays targeting a variety of viral families that are pathogens in non-human primates. We have also developed and further improved a computer program and website to facilitate the design of CODEHOP PCR primers. Here, we detail the method for the development of pathogen-specific CODEHOP PCR assays using the papillomavirus family as a target. Papillomaviruses constitute a diverse virus family infecting a wide variety of mammalian species, including humans and non-human primates. We demonstrate that our pan-papillomavirus CODEHOP assay is broadly reactive with all major branches of the virus family and show its utility in identifying a novel non-human primate papillomavirus in cynomolgus macaques.

  10. Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates.

    PubMed

    Wang, Qidi; Zhang, Lianfeng; Kuwahara, Kazuhiko; Li, Li; Liu, Zijie; Li, Taisheng; Zhu, Hua; Liu, Jiangning; Xu, Yanfeng; Xie, Jing; Morioka, Hiroshi; Sakaguchi, Nobuo; Qin, Chuan; Liu, Gang

    2016-05-13

    Severe acute respiratory syndrome (SARS) is caused by a coronavirus (SARS-CoV) and has the potential to threaten global public health and socioeconomic stability. Evidence of antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro and in non-human primates clouds the prospects for a safe vaccine. Using antibodies from SARS patients, we identified and characterized SARS-CoV B-cell peptide epitopes with disparate functions. In rhesus macaques, the spike glycoprotein peptides S471-503, S604-625, and S1164-1191 elicited antibodies that efficiently prevented infection in non-human primates. In contrast, peptide S597-603 induced antibodies that enhanced infection both in vitro and in non-human primates by using an epitope sequence-dependent (ESD) mechanism. This peptide exhibited a high level of serological reactivity (64%), which resulted from the additive responses of two tandem epitopes (S597-603 and S604-625) and a long-term human B-cell memory response with antisera from convalescent SARS patients. Thus, peptide-based vaccines against SARS-CoV could be engineered to avoid ADE via elimination of the S597-603 epitope. We provide herein an alternative strategy to prepare a safe and effective vaccine for ADE of viral infection by identifying and eliminating epitope sequence-dependent enhancement of viral infection.

  11. Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates

    PubMed Central

    Bell, Peter; Wang, Lili; Gao, Guangping; Haskins, Mark E.; Tarantal, Alice F.; McCarter, Robert J.; Zhu, Yanqing; Yu, Hongwei; Wilson, James M.

    2011-01-01

    Gene transfer vectors based on adeno-associated virus 8 (AAV8) are highly efficient in liver transduction and can be easily administered by intravenous injection. In mice, AAV8 transduces predominantly hepatocytes near central veins and yields lower transduction levels in hepatocytes in periportal regions. This transduction bias has important implications for gene therapy that aims to correct metabolic liver enzymes because metabolic zonation along the porto-central axis requires the expression of therapeutic proteins within the zone where they are normally localized. In the present study we compared the expression pattern of AAV8 expressing green fluorescent protein (GFP) in liver between mice, dogs, and non-human primates. We confirmed the pericentral dominance in transgene expression in mice with AAV8 when the liver-specific thyroid hormone-binding globulin (TBG) promoter was used but also observed the same expression pattern with the ubiquitous chicken β-actin (CB) and cytomegalovirus (CMV) promoters, suggesting that transduction zonation is not caused by promoter specificity. Predominantly pericentral expression was also found in dogs injected with AAV8. In contrast, in cynomolgus and rhesus macaques the expression pattern from AAV vectors was reversed, i.e. transgene expression was most intense around portal areas and less intense or absent around central veins. Infant rhesus macaques as well as newborn mice injected with AAV8 however showed a random distribution of transgene expression with neither portal nor central transduction bias. Based on the data in monkeys, adult humans treated with AAV vectors are predicted to also express transgenes predominantly in periportal regions whereas infants are likely to show a uniform transduction pattern in liver. PMID:21778099

  12. Social complexity parallels vocal complexity: a comparison of three non-human primate species.

    PubMed

    Bouchet, Hélène; Blois-Heulin, Catherine; Lemasson, Alban

    2013-01-01

    Social factors play a key role in the structuring of vocal repertoires at the individual level, notably in non-human primates. Some authors suggested that, at the species level too, social life may have driven the evolution of communicative complexity, but this has rarely been empirically tested. Here, we use a comparative approach to address this issue. We investigated vocal variability, at both the call type and the repertoire levels, in three forest-dwelling species of Cercopithecinae presenting striking differences in their social systems, in terms of social organization as well as social structure. We collected female call recordings from twelve De Brazza's monkeys (Cercopithecus neglectus), six Campbell's monkeys (Cercopithecus campbelli) and seven red-capped mangabeys (Cercocebus torquatus) housed in similar conditions. First, we noted that the level of acoustic variability and individual distinctiveness found in several call types was related to their importance in social functioning. Contact calls, essential to intra-group cohesion, were the most individually distinctive regardless of the species, while threat calls were more structurally variable in mangabeys, the most "despotic" of our three species. Second, we found a parallel between the degree of complexity of the species' social structure and the size, diversity, and usage of its vocal repertoire. Mangabeys (most complex social structure) called twice as often as guenons and displayed the largest and most complex repertoire. De Brazza's monkeys (simplest social structure) displayed the smallest and simplest repertoire. Campbell's monkeys displayed an intermediate pattern. Providing evidence of higher levels of vocal variability in species presenting a more complex social system, our results are in line with the theory of a social-vocal coevolution of communicative abilities, opening new perspectives for comparative research on the evolution of communication systems in different animal taxa.

  13. The genetic toxicology of methylphenidate hydrochloride in non-human primates.

    PubMed

    Morris, Suzanne M; Dobrovolsky, Vasily N; Shaddock, Joseph G; Mittelstaedt, Roberta A; Bishop, Michelle E; Manjanatha, Mugimane G; Shelton, Sharon D; Doerge, Daniel R; Twaddle, Nathan C; Chen, James J; Lin, Chien-Ju; Paule, Merle G; Slikker, William; Hotchkiss, Charlotte E; Petibone, Dayton; Tucker, James D; Mattison, Donald R

    2009-02-19

    The studies presented in this work were designed to evaluate the genetic toxicity of methylphenidate hydrochloride (MPH) in non-human primates (NHP) using a long-term, chronic dosing regimen. Thus, approximately two-year old, male rhesus monkeys of Indian origin were orally exposed to MPH diluted in the electrolyte replenisher, Prang, five days per week over a 20-month period. There were 10 animals per dose group and the doses were (1) control, Prang only, (2) low, 0.15 mg/kg of MPH twice per day increased to 2.5mg/kg twice per day and (3) high, 1.5 mg/kg of MPH twice per day increased to 12.5 mg/kg twice per day. Blood samples were obtained from each animal to determine the base-line serum levels of MPH and the major metabolite of MPH in NHP, ritalinic acid (RA). In addition, the base-line frequency of micronucleated erythrocytes (MN-RETs) by flow cytometry, HPRT mutants by a lymphocyte cloning assay, and chromosome aberrations by FISH painting were determined from peripheral blood samples. Once dosing began, the serum levels of MPH and its major metabolite, RA, were determined monthly. The MN-RET frequency and health parameters (CBC, serum chemistries) were also determined monthly. HPRT mutant and chromosome aberration frequencies were measured every three months. CBC values and serum chemistries, with the exception of alanine amino transferase, were within normal limits over the course of drug exposure. The final plasma levels of MPH were similar to those produced by the pediatric dose of 0.3 microg/ml. No significant increases in the frequencies of MN-RETs, HPRT mutants, or chromosome aberrations were detected in the treated animals compared to the control animals over the 20-month exposure period.

  14. Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi in Captive Non-Human Primates in Qinling Mountains

    PubMed Central

    Du, Shuai-Zhi; Zhao, Guang-Hui; Shao, Jun-Feng; Fang, Yan-Qin; Tian, Ge-Ru; Zhang, Long-Xian; Wang, Rong-Jun; Wang, Hai-Yan; Qi, Meng; Yu, San-Ke

    2015-01-01

    Non-human primates (NHPs) are confirmed as reservoirs of Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi. In this study, 197 fresh fecal samples from 8 NHP species in Qinling Mountains, northwestern China, were collected and examined using multilocus sequence typing (MLST) method. The results showed that 35 (17.8%) samples were positive for tested parasites, including Cryptosporidium spp. (3.0%), G. intestinalis (2.0%), and E. bieneusi (12.7%). Cryptosporidium spp. were detected in 6 fecal samples of Macaca mulatta, and were identified as C. parvum (n=1) and C. andersoni (n=5). Subtyping analysis showed Cryptosporidium spp. belonged to the C. andersoni MLST subtype (A4, A4, A4, and A1) and C. parvum 60 kDa glycoprotein (gp60) subtype IId A15G2R1. G. intestinalis assemblage E was detected in 3 M. mulatta and 1 Saimiri sciureus. Intra-variations were observed at the triose phosphate isomerase (tpi), beta giardin (bg), and glutamate dehydrogenase (gdh) loci, with 3, 1, and 2 new subtypes found in respective locus. E. bieneusi was found in Cercopithecus neglectus (25.0%), Papio hamadrayas (16.7%), M. mulatta (16.3%), S. sciureus (10%), and Rhinopithecus roxellana (9.5%), with 5 ribosomal internal transcribed spacer (ITS) genotypes: 2 known genotypes (D and BEB6) and 3 novel genotypes (MH, XH, and BSH). These findings indicated the presence of zoonotic potential of Cryptosporidium spp. and E. bieneusi in NHPs in Qinling Mountains. This is the first report of C. andersoni in NHPs. The present study provided basic information for control of cryptosporidiosis, giardiasis, and microsporidiosis in human and animals in this area. PMID:26323837

  15. Cortico-basal ganglia circuits involved in different motivation disorders in non-human primates.

    PubMed

    Sgambato-Faure, Véronique; Worbe, Yulia; Epinat, Justine; Féger, Jean; Tremblay, Léon

    2016-01-01

    The ventral striatum (VS) is of particular interest in the study of neuropsychiatric disorders. In this study, performed on non-human primates, we associated local perturbation with monosynaptic axonal tracer injection into medial, central and lateral VS to characterize anatomo-functional circuits underlying the respective expression of sexual manifestations, stereotyped behaviors and hypoactive state associated with loss of food motivation. For the three behavioral effects, we demonstrated the existence of three distinct cortico-basal ganglia (BG) circuits that were topographically organized and overlapping at some cortical (orbitofrontal cortex, anterior cingulate cortex) and subcortical (caudal levels of BG) levels, suggesting interactions between motivation domains. Briefly, erection was associated with a circuit involving the orbitofrontal cortex, medial prefrontal cortex (areas 10, 11) and limbic parts of BG, i.e. medial parts of the pallidal complex and the substantia nigra pars reticulata (SNr). Stereotyped behavior was linked to a circuit involving the lateral orbitofrontal cortex (area 12/47) and limbic parts of the pallidal complex and of the SNr, while the apathetic state was underlined by a circuit involving not only the orbital and medial prefrontal cortex but also the lateral prefrontal cortex (area 8, 45), the anterior insula and the lateral parts of the medial pallidal complex and of the ventro-medial SNr. For the three behavioral effects, the cortico-BG circuits mainly involved limbic regions of the external and internal pallidum, as well as the limbic part of the substantia nigra pars reticulata (SNr), suggesting the involvement of both direct and indirect striatal pathways and both output BG structures. As these motivation disorders could still be induced in dopamine (DA)-depleted monkeys, we suggest that DA issued from the substantia nigra pars compacta (SNc) modulates their expression rather than causes them. Finally, this study may give some

  16. Social complexity parallels vocal complexity: a comparison of three non-human primate species

    PubMed Central

    Bouchet, Hélène; Blois-Heulin, Catherine; Lemasson, Alban

    2013-01-01

    Social factors play a key role in the structuring of vocal repertoires at the individual level, notably in non-human primates. Some authors suggested that, at the species level too, social life may have driven the evolution of communicative complexity, but this has rarely been empirically tested. Here, we use a comparative approach to address this issue. We investigated vocal variability, at both the call type and the repertoire levels, in three forest-dwelling species of Cercopithecinae presenting striking differences in their social systems, in terms of social organization as well as social structure. We collected female call recordings from twelve De Brazza's monkeys (Cercopithecus neglectus), six Campbell's monkeys (Cercopithecus campbelli) and seven red-capped mangabeys (Cercocebus torquatus) housed in similar conditions. First, we noted that the level of acoustic variability and individual distinctiveness found in several call types was related to their importance in social functioning. Contact calls, essential to intra-group cohesion, were the most individually distinctive regardless of the species, while threat calls were more structurally variable in mangabeys, the most “despotic” of our three species. Second, we found a parallel between the degree of complexity of the species' social structure and the size, diversity, and usage of its vocal repertoire. Mangabeys (most complex social structure) called twice as often as guenons and displayed the largest and most complex repertoire. De Brazza's monkeys (simplest social structure) displayed the smallest and simplest repertoire. Campbell's monkeys displayed an intermediate pattern. Providing evidence of higher levels of vocal variability in species presenting a more complex social system, our results are in line with the theory of a social-vocal coevolution of communicative abilities, opening new perspectives for comparative research on the evolution of communication systems in different animal taxa. PMID

  17. Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi in Captive Non-Human Primates in Qinling Mountains.

    PubMed

    Du, Shuai-Zhi; Zhao, Guang-Hui; Shao, Jun-Feng; Fang, Yan-Qin; Tian, Ge-Ru; Zhang, Long-Xian; Wang, Rong-Jun; Wang, Hai-Yan; Qi, Meng; Yu, San-Ke

    2015-08-01

    Non-human primates (NHPs) are confirmed as reservoirs of Cryptosporidium spp., Giardia intestinalis, and Enterocytozoon bieneusi. In this study, 197 fresh fecal samples from 8 NHP species in Qinling Mountains, northwestern China, were collected and examined using multilocus sequence typing (MLST) method. The results showed that 35 (17.8%) samples were positive for tested parasites, including Cryptosporidium spp. (3.0%), G. intestinalis (2.0%), and E. bieneusi (12.7%). Cryptosporidium spp. were detected in 6 fecal samples of Macaca mulatta, and were identified as C. parvum (n=1) and C. andersoni (n=5). Subtyping analysis showed Cryptosporidium spp. belonged to the C. andersoni MLST subtype (A4, A4, A4, and A1) and C. parvum 60 kDa glycoprotein (gp60) subtype IId A15G2R1. G. intestinalis assemblage E was detected in 3 M. mulatta and 1 Saimiri sciureus. Intra-variations were observed at the triose phosphate isomerase (tpi), beta giardin (bg), and glutamate dehydrogenase (gdh) loci, with 3, 1, and 2 new subtypes found in respective locus. E. bieneusi was found in Cercopithecus neglectus (25.0%), Papio hamadrayas (16.7%), M. mulatta (16.3%), S. sciureus (10%), and Rhinopithecus roxellana (9.5%), with 5 ribosomal internal transcribed spacer (ITS) genotypes: 2 known genotypes (D and BEB6) and 3 novel genotypes (MH, XH, and BSH). These findings indicated the presence of zoonotic potential of Cryptosporidium spp. and E. bieneusi in NHPs in Qinling Mountains. This is the first report of C. andersoni in NHPs. The present study provided basic information for control of cryptosporidiosis, giardiasis, and microsporidiosis in human and animals in this area.

  18. Do robots have goals? How agent cues influence action understanding in non-human primates.

    PubMed

    Kupferberg, Aleksandra; Glasauer, Stefan; Burkart, Judith M

    2013-06-01

    The capacity to understand goals and intentions emerges early and universally in humans and is a basic precondition for the interpretation and prediction of others' actions, be it other humans, animals, or even robots. It is unclear, however, how this goal attribution system is acquired, in particular with regard to the role of prior experience with the actor and visual characteristics that are necessary. In four preferential looking time experiments we examined how familiarity, appearance, and movement of different agents influence the capability of marmosets to perceive the behavior of these agents as goal directed. To this end we compared the monkeys' reactions to the same goal-directed actions performed by four different agents: a human actor, a conspecific, a monkey-like small robot, and a black box. The results showed that monkeys attributed goals to the human actor, the conspecific, and the robot, but not the box. Thus, the monkeys extended their capacity for goal attribution not only to familiar agents, but also to agents not previously encountered, provided that they had some conspecific-like features. Our results suggest that in non-human primates, the system for goal attribution does not require previous experience with a specific agent or agent-category, as long as it exhibits certain visual characteristics like face, body or legs. Furthermore, the results suggest that the capacity to attribute goals emerged very early during evolution and, at least in marmoset monkeys, does not necessarily require pre-learned associations in order to fulfill its function when dealing with unfamiliar agents.

  19. Morphine Produces Immunosuppressive Effects in Non-human Primates at the Proteomic and Cellular Levels

    SciTech Connect

    Brown, Joseph N.; Ortiz, Gabriel M.; Angel, Thomas E.; Jacobs, Jon M.; Gritsenko, Marina A.; Chan, Eric Y.; Purdy, David E.; Murnane, Robert D.; Larsen, Kay; Palermo, Robert E.; Shukla, Anil K.; Clauss, Therese RW; Katze, Michael G.; McCune, Joseph M.; Smith, Richard D.

    2012-05-11

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. As a prelude to understanding how these changes might interact with lentiviral infection in vivo, animals from two non-human primate (NHP) species [African green monkey (AGMs) and pigtailed macaque (PTs)] were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g., lymph node, colon, cerebrospinal fluid (CSF), and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an inter-organ, inter-individual, and inter-species basis. In both species, morphine was associated with decreased levels of (Ki-67+) T cell activation but with only minimal changes in overall T cell counts, neutrophil counts, and NK cells counts. While changes in T cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in the lymph node, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the interplay between opioid abuse and the response to infection with agents such as the human immunodeficiency virus, type 1 (HIV).

  20. Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury.

    PubMed

    Slotkin, Jonathan R; Pritchard, Christopher D; Luque, Brian; Ye, Janice; Layer, Richard T; Lawrence, Mathew S; O'Shea, Timothy M; Roy, Roland R; Zhong, Hui; Vollenweider, Isabel; Edgerton, V Reggie; Courtine, Grégoire; Woodard, Eric J; Langer, Robert

    2017-04-01

    Tissue loss significantly reduces the potential for functional recovery after spinal cord injury. We previously showed that implantation of porous scaffolds composed of a biodegradable and biocompatible block copolymer of Poly-lactic-co-glycolic acid and Poly-l-lysine improves functional recovery and reduces spinal cord tissue injury after spinal cord hemisection injury in rats. Here, we evaluated the safety and efficacy of porous scaffolds in non-human Old-World primates (Chlorocebus sabaeus) after a partial and complete lateral hemisection of the thoracic spinal cord. Detailed analyses of kinematics and muscle activity revealed that by twelve weeks after injury fully hemisected monkeys implanted with scaffolds exhibited significantly improved recovery of locomotion compared to non-implanted control animals. Twelve weeks after injury, histological analysis demonstrated that the spinal cords of monkeys with a hemisection injury implanted with scaffolds underwent appositional healing characterized by a significant increase in remodeled tissue in the region of the hemisection compared to non-implanted controls. The number of glial fibrillary acidic protein immunopositive astrocytes was diminished within the inner regions of the remodeled tissue layer in treated animals. Activated macrophage and microglia were present diffusely throughout the remodeled tissue and concentrated at the interface between the preserved spinal cord tissue and the remodeled tissue layer. Numerous unphosphorylated neurofilament H and neuronal growth associated protein positive fibers and myelin basic protein positive cells may indicate neural sprouting inside the remodeled tissue layer of treated monkeys. These results support the safety and efficacy of polymer scaffolds in a primate model of acute spinal cord injury. A device substantially similar to the device described here is the subject of an ongoing human clinical trial.

  1. The high-affinity receptor for IgG, FcγRI, of humans and non-human primates.

    PubMed

    Chenoweth, Alicia M; Trist, Halina M; Tan, Peck-Szee; Wines, Bruce D; Hogarth, P Mark

    2015-11-01

    Non-human primate (NHP) models, especially involving macaques, are considered important models of human immunity and have been essential in preclinical testing for vaccines and therapeutics. Despite this, much less characterization of macaque Fc receptors has occurred compared to humans or mice. Much of the characterization of macaque Fc receptors so far has focused on the low-affinity Fc receptors, particularly FcγRIIIa. From these studies, it is clear that there are distinct differences between the human and macaque low-affinity receptors and their interaction with human IgG. Relatively little work has been performed on the high-affinity IgG receptor, FcγRI, especially in NHPs. This review will focus on what is currently known of how FcγRI interacts with IgG, from mutation studies and recent crystallographic studies of human FcγRI, and how amino acid sequence differences in the macaque FcγRI may affect this interaction. Additionally, this review will look at the functional consequences of differences in the amino acid sequences between humans and macaques.

  2. Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates

    PubMed Central

    Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

    2017-01-01

    Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus, spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (rs=0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (rs=0.56) and hippocampus (rs=−0.62) or septum (rs=−0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes. PMID:28039490

  3. Scanning electron microscopy of chronically implanted intracortical microelectrode arrays in non-human primates

    PubMed Central

    Barrese, James C; Aceros, Juan; Donoghue, John P

    2016-01-01

    Objective Signal attenuation is a major problem facing intracortical sensors for chronic neuroprosthetic applications. Many studies suggest that failure is due to gliosis around the electrode tips, however, mechanical and material causes of failure are often overlooked. The purpose of this study was to investigate the factors contributing to progressive signal decline by using scanning electron microscopy (SEM) to visualize structural changes in chronically implanted arrays and histology to examine the tissue response at corresponding implant sites. Approach We examined eight chronically implanted intracortical microelectrode arrays (MEAs) explanted from non-human primates at times ranging from 37 to 1051 days post-implant. We used SEM, in vivo neural recordings, and histology (GFAP, Iba-1, NeuN). Three MEAs that were never implanted were also imaged as controls. Main results SEM revealed progressive corrosion of the platinum electrode tips and changes to the underlying silicon. The parylene insulation was prone to cracking and delamination, and in some instances the silicone elastomer also delaminated from the edges of the MEA. Substantial tissue encapsulation was observed and was often seen growing into defects in the platinum and parylene. These material defects became more common as the time in vivo increased. Histology at 37 and 1051 days post-implant showed gliosis, disruption of normal cortical architecture with minimal neuronal loss, and high Iba-1 reactivity, especially within the arachnoid and dura. Electrode tracts were either absent or barely visible in the cortex at 1051 days, but were seen in the fibrotic encapsulation material suggesting that the MEAs were lifted out of the brain. Neural recordings showed a progressive drop in impedance, signal amplitude, and viable channels over time. Significance These results provide evidence that signal loss in MEAs is truly multifactorial. Gliosis occurs in the first few months after implantation but does not

  4. Scanning electron microscopy of chronically implanted intracortical microelectrode arrays in non-human primates

    NASA Astrophysics Data System (ADS)

    Barrese, James C.; Aceros, Juan; Donoghue, John P.

    2016-04-01

    Objective. Signal attenuation is a major problem facing intracortical sensors for chronic neuroprosthetic applications. Many studies suggest that failure is due to gliosis around the electrode tips, however, mechanical and material causes of failure are often overlooked. The purpose of this study was to investigate the factors contributing to progressive signal decline by using scanning electron microscopy (SEM) to visualize structural changes in chronically implanted arrays and histology to examine the tissue response at corresponding implant sites. Approach. We examined eight chronically implanted intracortical microelectrode arrays (MEAs) explanted from non-human primates at times ranging from 37 to 1051 days post-implant. We used SEM, in vivo neural recordings, and histology (GFAP, Iba-1, NeuN). Three MEAs that were never implanted were also imaged as controls. Main results. SEM revealed progressive corrosion of the platinum electrode tips and changes to the underlying silicon. The parylene insulation was prone to cracking and delamination, and in some instances the silicone elastomer also delaminated from the edges of the MEA. Substantial tissue encapsulation was observed and was often seen growing into defects in the platinum and parylene. These material defects became more common as the time in vivo increased. Histology at 37 and 1051 days post-implant showed gliosis, disruption of normal cortical architecture with minimal neuronal loss, and high Iba-1 reactivity, especially within the arachnoid and dura. Electrode tracts were either absent or barely visible in the cortex at 1051 days, but were seen in the fibrotic encapsulation material suggesting that the MEAs were lifted out of the brain. Neural recordings showed a progressive drop in impedance, signal amplitude, and viable channels over time. Significance. These results provide evidence that signal loss in MEAs is truly multifactorial. Gliosis occurs in the first few months after implantation but does

  5. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates

    NASA Astrophysics Data System (ADS)

    Barrese, James C.; Rao, Naveen; Paroo, Kaivon; Triebwasser, Corey; Vargas-Irwin, Carlos; Franquemont, Lachlan; Donoghue, John P.

    2013-12-01

    systematic early increases, which did not appear to affect recording quality, followed by a slow decline over years. The combination of slowly falling impedance and signal quality in these arrays indicates that insulating material failure is the most significant factor. Significance. This is the first long-term failure mode analysis of an emerging BCI technology in a large series of non-human primates. The classification system introduced here may be used to standardize how neuroprosthetic failure modes are evaluated. The results demonstrate the potential for these arrays to record for many years, but achieving reliable sensors will require replacing connectors with implantable wireless systems, controlling the meningeal reaction, and improving insulation materials. These results will focus future research in order to create clinical neuroprosthetic sensors, as well as valuable research tools, that are able to safely provide reliable neural signals for over a decade.

  6. Intravenously injected Newcastle disease virus in non-human primates is safe to use for oncolytic virotherapy.

    PubMed

    Buijs, P R A; van Amerongen, G; van Nieuwkoop, S; Bestebroer, T M; van Run, P R W A; Kuiken, T; Fouchier, R A M; van Eijck, C H J; van den Hoogen, B G

    2014-11-01

    Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic potential. Detailed preclinical information regarding the safety of oncolytic NDV is scarce. In this study, we evaluated the toxicity, biodistribution and shedding of intravenously injected oncolytic NDVs in non-human primates (Macaca fascicularis). Two animals were injected with escalating doses of a non-recombinant vaccine strain, a recombinant lentogenic strain or a recombinant mesogenic strain. To study transmission, naive animals were co-housed with the injected animals. Injection with NDV did not lead to severe illness in the animals or abnormalities in hematologic or biochemistry measurements. Injected animals shed low amounts of virus, but this did not lead to seroconversion of the contact animals. Postmortem evaluation demonstrated no pathological changes or evidence of virus replication. This study demonstrates that NDV generated in embryonated chicken eggs is safe for intravenous administration to non-human primates. In addition, our study confirmed results from a previous report that naïve primate and human sera are able to neutralize egg-generated NDV. We discuss the implications of these results for our study and the use of NDV for virotherapy.

  7. A comparative study of the trabecular bony architecture of the talus in humans, non-human primates, and Australopithecus.

    PubMed

    DeSilva, Jeremy M; Devlin, Maureen J

    2012-09-01

    This study tested the hypothesis that talar trabecular microarchitecture reflects the loading patterns in the primate ankle joint, to determine whether talar trabecular morphology might be useful for inferring locomotor behavior in fossil hominins. Trabecular microarchitecture was quantified in the anteromedial, anterolateral, posteromedial, and posterolateral quadrants of the talar body in humans and non-human primates using micro-computed tomography. Trabecular bone parameters, including bone volume fraction, trabecular number and thickness, and degree of anisotropy differed between primates, but not in a manner entirely consistent with hypotheses derived from locomotor kinematics. Humans have highly organized trabecular struts across the entirety of the talus, consistent with the compressive loads incurred during bipedal walking. Chimpanzees possess a high bone volume fraction, consisting of plate-like trabecular struts. Orangutan tali are filled with a high number of thin, connected trabeculae, particularly in the anterior portion of the talus. Gorillas and baboons have strikingly similar internal architecture of the talus. Intraspecific analyses revealed no regional differences in trabecular architecture unique to bipedal humans. Of the 22 statistically significant regional differences in the human talus, all can also be found in other primates. Trabecular thickness, number, spacing, and connectivity density had the same regional relationship in the talus of humans, chimpanzees, gorillas, and baboons, suggesting a deeply conserved architecture in the primate talus. Australopithecus tali are human-like in most respects, differing most notably in having more oriented struts in the posteromedial quadrant of the body compared with the posterolateral quadrant. Though this result could mean that australopiths loaded their ankles in a unique manner during bipedal gait, the regional variation in degree of anisotropy was similar in humans, chimpanzees, and gorillas

  8. Primate Models in Organ Transplantation

    PubMed Central

    Anderson, Douglas J.; Kirk, Allan D.

    2013-01-01

    Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic- and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed. PMID:24003248

  9. First report of yellow fever virus in non-human primates in the State of Paraná, Brazil.

    PubMed

    Tranquilin, Marcos Vinícius; Lehmkuhl, Ricardo Coelho; Maron, Angela; Silva, Lineu Roberto da; Ziliotto, Liane; Seki, Meire Christina; Salomon, Gabriela Ronchi; Carrasco, Adriano de Oliveira Torres

    2013-01-01

    Sylvatic yellow fever is a zoonosis associated mainly with wild animals, especially those in the genus Alouatta, that act as the source of infection. Once infected, these animals pass the disease on to humans by way of an infected mosquito belonging to the genera Aedes, Haemagogus, or Sabethes. The present study is the first report of a case of yellow fever in non-human primates (NHP) in the State of Paraná, Brazil. After the case was diagnosed, several prophylactic measures were adopted to prevent outbreaks of the disease in humans.

  10. Is Alpha-Synuclein Loss-of-Function a Contributor to Parkinsonian Pathology? Evidence from Non-human Primates

    PubMed Central

    Collier, Timothy J.; Redmond, D. Eugene; Steece-Collier, Kathy; Lipton, Jack W.; Manfredsson, Fredric P.

    2016-01-01

    Accumulation of alpha-synuclein (α-syn) in Lewy bodies and neurites of midbrain dopamine neurons is diagnostic for Parkinson's disease (PD), leading to the proposal that PD is a toxic gain-of-function synucleinopathy. Here we discuss the alternative viewpoint that α-syn displacement from synapses by misfolding and aggregation results in a toxic loss-of-function. In support of this hypothesis we provide evidence from our pilot study demonstrating that knockdown of endogenous α-syn in dopamine neurons of non-human primates reproduces the pattern of nigrostriatal degeneration characteristic of PD. PMID:26858591

  11. Bridging non-human primate correlates of protection to reassess the Anthrax Vaccine Adsorbed booster schedule in humans.

    PubMed

    Schiffer, Jarad M; Chen, Ligong; Dalton, Shannon; Niemuth, Nancy A; Sabourin, Carol L; Quinn, Conrad P

    2015-07-17

    Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved for use in humans as a priming series of 3 intramuscular (i.m.) injections (0, 1, 6 months; 3-IM) with boosters at 12 and 18 months, and annually thereafter for those at continued risk of infection. A reduction in AVA booster frequency would lessen the burden of vaccination, reduce the cumulative frequency of vaccine associated adverse events and potentially expand vaccine coverage by requiring fewer doses per schedule. Because human inhalation anthrax studies are neither feasible nor ethical, AVA efficacy estimates are determined using cross-species bridging of immune correlates of protection (COP) identified in animal models. We have previously reported that the AVA 3-IM priming series provided high levels of protection in non-human primates (NHP) against inhalation anthrax for up to 4 years after the first vaccination. Penalized logistic regressions of those NHP immunological data identified that anti-protective antigen (anti-PA) IgG concentration measured just prior to infectious challenge was the most accurate single COP. In the present analysis, cross-species logistic regression models of this COP were used to predict probability of survival during a 43 month study in humans receiving the current 3-dose priming and 4 boosters (12, 18, 30 and 42 months; 7-IM) and reduced schedules with boosters at months 18 and 42 only (5-IM), or at month 42 only (4-IM). All models predicted high survival probabilities for the reduced schedules from 7 to 43 months. The predicted survival probabilities for the reduced schedules were 86.8% (4-IM) and 95.8% (5-IM) at month 42 when antibody levels were lowest. The data indicated that 4-IM and 5-IM are both viable alternatives to the current AVA pre-exposure prophylaxis schedule.

  12. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates

    PubMed Central

    Barrese, James C; Rao, Naveen; Paroo, Kaivon; Triebwasser, Corey; Vargas-Irwin, Carlos; Franquemont, Lachlan; Donoghue, John P

    2016-01-01

    systematic early increases, which did not appear to affect recording quality, followed by a slow decline over years. The combination of slowly falling impedance and signal quality in these arrays indicate that insulating material failure is the most significant factor. Significance This is the first long-term failure mode analysis of an emerging BCI technology in a large series of non-human primates. The classification system introduced here may be used to standardize how neuroprosthetic failure modes are evaluated. The results demonstrate the potential for these arrays to record for many years, but achieving reliable sensors will require replacing connectors with implantable wireless systems, controlling the meningeal reaction, and improving insulation materials. These results will focus future research in order to create clinical neuroprosthetic sensors, as well as valuable research tools, that are able to safely provide reliable neural signals for over a decade. PMID:24216311

  13. Effects of metoprolol on epinephrine-induced takotsubo-like left ventricular dysfunction in non-human primates.

    PubMed

    Izumi, Yasukatsu; Okatani, Hideaki; Shiota, Masayuki; Nakao, Takafumi; Ise, Ryota; Kito, Go; Miura, Katsuyuki; Iwao, Hiroshi

    2009-05-01

    Takotsubo cardiomyopathy, alternatively known as stress cardiomyopathy, is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction. To elucidate the mechanism, we tried to make a new model of takotsubo-like cardiomyopathy in non-human primates. Echocardiography revealed that repeated intravenous infusion of epinephrine overdose in cynomolgus monkeys induced takotsubo-like cardiomyopathy, which is characterized by progressive left ventricle and depressed systolic function with severe hypokinesis in apical regions and hyperkinesis in the basal region. Although this cardiac dysfunction almost normalized after a month even without any treatment, metoprolol, a beta-blocker, improved the decreased ejection fraction earlier than in the control. Luxol fast blue staining, which is useful for estimating myocytolysis, showed that increased myocytolysis was observed in the apical ventricle of the epinephrine-infused heart. Metoprolol diminished epinephrine-induced cardiomyocytolysis. To explain the mechanism of takotsubo myopathy and the effect of metoprolol, gene expressions in apical or basal ventricle were compared. Heart failure-related genes, such as brain natriuretic peptide, connective tissue growth factor and osteopontin; calcium signaling-related genes, such as ryanodine receptor 2, sarcoendoplasmic reticulum Ca(2+)-ATPase 2A2 and adenylate cyclase 7; renin-angiotensin system-related genes, such as angiotensinogen, angiotensin II receptor, type 1 and type 2; and mitochondria-related genes, such as peroxisome proliferator-activated receptor-gamma co-activator-1alpha, cytochrome c and transcription factor A mitochondrial, were significantly changed at the apical ventricle rather than at the basal ventricle. The changes of some genes improved with metoprolol treatment. These results indicate that this model is valuable in understanding the pathogenesis of takotsubo cardiomyopathy and the effectivity of beta-blockers.

  14. Approaches to optical neuromodulation from rodents to non-human primates by integrated optoelectronic devices.

    PubMed

    Wang, Jing; Ozden, Ilker; Diagne, Mohamed; Wagner, Fabien; Borton, David; Brush, Benjamin; Agha, Naubahar; Burwell, Rebecca; Sheinberg, David; Diester, Ilka; Deisseroth, Karl; Nurmikko, Arto

    2011-01-01

    Methods on rendering neurons in the central nervous system to be light responsive has led to a boom in using optical neuromodulation as a new approach for controlling brain states and understanding neural circuits. In addition to the developing versatility to "optogenetically" labeling of neural cells and their subtypes by microbiological methods, parallel efforts are under way to design and implement optoelectronic devices to achieve simultaneous optical neuromodulation and electrophysiological recording with high spatial and temporal resolution. Such new device-based technologies need to be developed for full exploitation of the promise of optogenetics. In this paper we present single- and multi-element optoelectronic devices developed in our laboratories. The single-unit element, namely the coaxial optrode, was utilized to characterize the neural responses in optogenetically modified rodent and primate models. Furthermore, the multi-element device, integrating the optrode with a 6×6 microelectrode array, was used to characterize the spatiotemporal spread of neural activity in response to single-site optical stimulation in freely moving rats. We suggest that the particular approaches we employed can lead to the emergence of methods where spatio-temporal optical modulation is integrated with real-time read out from neural populations.

  15. Using naturalistic utterances to investigate vocal communication processing and development in human and non-human primates.

    PubMed

    Talkington, William J; Taglialatela, Jared P; Lewis, James W

    2013-11-01

    Humans and several non-human primates possess cortical regions that are most sensitive to vocalizations produced by their own kind (conspecifics). However, the use of speech and other broadly defined categories of behaviorally relevant natural sounds has led to many discrepancies regarding where voice-sensitivity occurs, and more generally the identification of cortical networks, "proto-networks" or protolanguage networks, and pathways that may be sensitive or selective for certain aspects of vocalization processing. In this prospective review we examine different approaches for exploring vocal communication processing, including pathways that may be, or become, specialized for conspecific utterances. In particular, we address the use of naturally produced non-stereotypical vocalizations (mimicry of other animal calls) as another category of vocalization for use with human and non-human primate auditory systems. We focus this review on two main themes, including progress and future ideas for studying vocalization processing in great apes (chimpanzees) and in very early stages of human development, including infants and fetuses. Advancing our understanding of the fundamental principles that govern the evolution and early development of cortical pathways for processing non-verbal communication utterances is expected to lead to better diagnoses and early intervention strategies in children with communication disorders, improve rehabilitation of communication disorders resulting from brain injury, and develop new strategies for intelligent hearing aid and implant design that can better enhance speech signals in noisy environments. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives".

  16. Molecular Detection of Plasmodium malariae/Plasmodium brasilianum in Non-Human Primates in Captivity in Costa Rica

    PubMed Central

    Fuentes-Ramírez, Alicia; Jiménez-Soto, Mauricio; Castro, Ruth; Romero-Zuñiga, Juan José

    2017-01-01

    One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium using thick blood smears, semi-nested multiplex polymerase chain reaction (SnM-PCR) for species differentiation, cloning and sequencing for confirmation. Using thick blood smears, two samples were determined to contain the Plasmodium malariae parasite, with SnM-PCR, a total of five (3.3%) samples were positive to P. malariae, cloning and sequencing confirmed both smear samples as P. malariae. One sample amplified a larger and conserved region of 18S rDNA for the genus Plasmodium and sequencing confirmed the results obtained microscopically and through SnM-PCR tests. Sequencing and construction of a phylogenetic tree of this sample revealed that the P. malariae/P. brasilianum parasite (GenBank KU999995) found in a howler monkey (Alouatta palliata) is identical to that recently reported in humans in Costa Rica. The SnM-PCR detected P. malariae/P. brasilianum parasite in different non-human primate species in captivity and in various regions of the southern Atlantic and Pacific coast of Costa Rica. The similarity of the sequences of parasites found in humans and a monkey suggests that monkeys may be acting as reservoirs of P.malariae/P. brasilianum, for which reason it is important, to include them in control and eradication programs. PMID:28125696

  17. Good gibbons and evil macaques: a historical review on cognitive features of non-human primates in Chinese traditional culture.

    PubMed

    Zhang, Peng

    2015-07-01

    For several thousand years the ancient Chinese have accumulated rich knowledge, in the form of written literature and folklore, on the non-human primates widely distributed in China. I have used critical text analysis and discourse analysis to clarify when and how ancient Chinese distinguished gibbons from macaques. I divided the progress into four main stages, the Pre-Shang to Shang dynasty (before 1046 BC), the Zhou to Han dynasty (1046 BC-220 AD), the six dynasties to Song dynasty (220-1279 AD), and the Yuan to Qing dynasties (1279-1840 AD). I found that China's traditional cognition of gibbons and macaques emphasized the appearance of animals, organoleptic performance, or even whether or not their behavior was "moral". They described them as human-like animals by ethical standards but ignored the species itself. This kind of cognitive style actually embodies the "pursuit of goodness", which is the feature of Chinese traditional culture. This study presents some original views on Chinese traditional knowledge of non-human primates.

  18. Molecular Detection of Plasmodium malariae/Plasmodium brasilianum in Non-Human Primates in Captivity in Costa Rica.

    PubMed

    Fuentes-Ramírez, Alicia; Jiménez-Soto, Mauricio; Castro, Ruth; Romero-Zuñiga, Juan José; Dolz, Gaby

    2017-01-01

    One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium using thick blood smears, semi-nested multiplex polymerase chain reaction (SnM-PCR) for species differentiation, cloning and sequencing for confirmation. Using thick blood smears, two samples were determined to contain the Plasmodium malariae parasite, with SnM-PCR, a total of five (3.3%) samples were positive to P. malariae, cloning and sequencing confirmed both smear samples as P. malariae. One sample amplified a larger and conserved region of 18S rDNA for the genus Plasmodium and sequencing confirmed the results obtained microscopically and through SnM-PCR tests. Sequencing and construction of a phylogenetic tree of this sample revealed that the P. malariae/P. brasilianum parasite (GenBank KU999995) found in a howler monkey (Alouatta palliata) is identical to that recently reported in humans in Costa Rica. The SnM-PCR detected P. malariae/P. brasilianum parasite in different non-human primate species in captivity and in various regions of the southern Atlantic and Pacific coast of Costa Rica. The similarity of the sequences of parasites found in humans and a monkey suggests that monkeys may be acting as reservoirs of P.malariae/P. brasilianum, for which reason it is important, to include them in control and eradication programs.

  19. Using naturalistic utterances to investigate vocal communication processing and development in human and non-human primates

    PubMed Central

    Talkington, William J.; Taglialatela, Jared P.; Lewis, James W.

    2013-01-01

    Humans and several non-human primates possess cortical regions that are most sensitive to vocalizations produced by their own kind (conspecifics). However, the use of speech and other broadly defined categories of behaviorally relevant natural sounds has led to many discrepancies regarding where voice-sensitivity occurs, and more generally the identification of cortical networks, “proto-networks” or protolanguage networks, and pathways that may be sensitive or selective for certain aspects of vocalization processing. In this prospective review we examine different approaches for exploring vocal communication processing, including pathways that may be, or become, specialized for conspecific utterances. In particular, we address the use of naturally produced non-stereotypical vocalizations (mimicry of other animal calls) as another category of vocalization for use with human and non-human primate auditory systems. We focus this review on two main themes, including progress and future ideas for studying vocalization processing in great apes (chimpanzees) and in very early stages of human development, including infants and fetuses. Advancing our understanding of the fundamental principles that govern the evolution and early development of cortical pathways for processing non-verbal communication utterances is expected to lead to better diagnoses and early intervention strategies in children with communication disorders, improve rehabilitation of communication disorders resulting from brain injury, and develop new strategies for intelligent hearing aid and implant design that can better enhance speech signals in noisy environments. PMID:23994296

  20. A Coaxial Optrode As Multifunction Write-Read Probe for Optogenetic Studies in Non-Human Primates

    PubMed Central

    Ozden, Ilker; Wang, Jing; Lu, Yao; May, Travis; Lee, Joonhee; Goo, Werapong; O’Shea, Daniel J.; Kalanithi, Paul; Diester, Ilka; Diagne, Mohamed; Deisseroth, Karl; Shenoy, Krishna V.; Nurmikko, Arto V.

    2013-01-01

    Background Advances in optogenetics have led to first reports of expression of light-gated ion-channels in non-human primates (NHPs). However, a major obstacle preventing effective application of optogenetics in NHPs and translation to optogenetic therapeutics is the absence of compatible multifunction optoelectronic probes for (1) precision light delivery, (2) low-interference electrophysiology, (3) protein fluorescence detection, and (4) repeated insertion with minimal brain trauma. New Method Here we describe a novel brain probe device, a “coaxial optrode”, designed to minimize brain tissue damage while microfabricated to perform simultaneous electrophysiology, light delivery and fluorescence measurements in the NHP brain. The device consists of a tapered, gold-coated optical fiber inserted in a polyamide tube. A portion of the gold coating is exposed at the fiber tip to allow electrophysiological recordings in addition to light delivery/collection at the tip. Results Coaxial optrode performance was demonstrated by experiments in rodents and NHPs, and characterized by computational models. The device mapped opsin expression in the brain and achieved precisely targeted optical stimulation and electrophysiology with minimal cortical damage. Comparison with Existing Methods Overall, combined electrical, optical and mechanical features of the coaxial optrode allowed a performance for NHP studies which was not possible with previously existing devices. Conclusions Coaxial optrode is currently being used in two NHP laboratories as a major tool to study brain function by inducing light modulated neural activity and behavior. By virtue of its design, the coaxial optrode can be extended for use as a chronic implant and multisite neural stimulation/recording. PMID:23867081

  1. Development of the first marmoset-specific DNA microarray (EUMAMA): a new genetic tool for large-scale expression profiling in a non-human primate

    PubMed Central

    Datson, Nicole A; Morsink, Maarten C; Atanasova, Srebrena; Armstrong, Victor W; Zischler, Hans; Schlumbohm, Christina; Dutilh, Bas E; Huynen, Martijn A; Waegele, Brigitte; Ruepp, Andreas; de Kloet, E Ronald; Fuchs, Eberhard

    2007-01-01

    Background The common marmoset monkey (Callithrix jacchus), a small non-endangered New World primate native to eastern Brazil, is becoming increasingly used as a non-human primate model in biomedical research, drug development and safety assessment. In contrast to the growing interest for the marmoset as an animal model, the molecular tools for genetic analysis are extremely limited. Results Here we report the development of the first marmoset-specific oligonucleotide microarray (EUMAMA) containing probe sets targeting 1541 different marmoset transcripts expressed in hippocampus. These 1541 transcripts represent a wide variety of different functional gene classes. Hybridisation of the marmoset microarray with labelled RNA from hippocampus, cortex and a panel of 7 different peripheral tissues resulted in high detection rates of 85% in the neuronal tissues and on average 70% in the non-neuronal tissues. The expression profiles of the 2 neuronal tissues, hippocampus and cortex, were highly similar, as indicated by a correlation coefficient of 0.96. Several transcripts with a tissue-specific pattern of expression were identified. Besides the marmoset microarray we have generated 3215 ESTs derived from marmoset hippocampus, which have been annotated and submitted to GenBank [GenBank: EF214838 – EF215447, EH380242 – EH382846]. Conclusion We have generated the first marmoset-specific DNA microarray and demonstrated its use to characterise large-scale gene expression profiles of hippocampus but also of other neuronal and non-neuronal tissues. In addition, we have generated a large collection of ESTs of marmoset origin, which are now available in the public domain. These new tools will facilitate molecular genetic research into this non-human primate animal model. PMID:17592630

  2. High-resolution imaging of the large non-human primate brain using microPET: a feasibility study

    NASA Astrophysics Data System (ADS)

    Naidoo-Variawa, S.; Hey-Cunningham, A. J.; Lehnert, W.; Kench, P. L.; Kassiou, M.; Banati, R.; Meikle, S. R.

    2007-11-01

    The neuroanatomy and physiology of the baboon brain closely resembles that of the human brain and is well suited for evaluating promising new radioligands in non-human primates by PET and SPECT prior to their use in humans. These studies are commonly performed on clinical scanners with 5 mm spatial resolution at best, resulting in sub-optimal images for quantitative analysis. This study assessed the feasibility of using a microPET animal scanner to image the brains of large non-human primates, i.e. papio hamadryas (baboon) at high resolution. Factors affecting image accuracy, including scatter, attenuation and spatial resolution, were measured under conditions approximating a baboon brain and using different reconstruction strategies. Scatter fraction measured 32% at the centre of a 10 cm diameter phantom. Scatter correction increased image contrast by up to 21% but reduced the signal-to-noise ratio. Volume resolution was superior and more uniform using maximum a posteriori (MAP) reconstructed images (3.2-3.6 mm3 FWHM from centre to 4 cm offset) compared to both 3D ordered subsets expectation maximization (OSEM) (5.6-8.3 mm3) and 3D reprojection (3DRP) (5.9-9.1 mm3). A pilot 18F-2-fluoro-2-deoxy-d-glucose ([18F]FDG) scan was performed on a healthy female adult baboon. The pilot study demonstrated the ability to adequately resolve cortical and sub-cortical grey matter structures in the baboon brain and improved contrast when images were corrected for attenuation and scatter and reconstructed by MAP. We conclude that high resolution imaging of the baboon brain with microPET is feasible with appropriate choices of reconstruction strategy and corrections for degrading physical effects. Further work to develop suitable correction algorithms for high-resolution large primate imaging is warranted.

  3. Detection of optogenetic stimulation in somatosensory cortex by non-human primates--towards artificial tactile sensation.

    PubMed

    May, Travis; Ozden, Ilker; Brush, Benjamin; Borton, David; Wagner, Fabien; Agha, Naubahar; Sheinberg, David L; Nurmikko, Arto V

    2014-01-01

    Neuroprosthesis research aims to enable communication between the brain and external assistive devices while restoring lost functionality such as occurs from stroke, spinal cord injury or neurodegenerative diseases. In future closed-loop sensorimotor prostheses, one approach is to use neuromodulation as direct stimulus to the brain to compensate for a lost sensory function and help the brain to integrate relevant information for commanding external devices via, e.g. movement intention. Current neuromodulation techniques rely mainly of electrical stimulation. Here we focus specifically on the question of eliciting a biomimetically relevant sense of touch by direct stimulus of the somatosensory cortex by introducing optogenetic techniques as an alternative to electrical stimulation. We demonstrate that light activated opsins can be introduced to target neurons in the somatosensory cortex of non-human primates and be optically activated to create a reliably detected sensation which the animal learns to interpret as a tactile sensation localized within the hand. The accomplishment highlighted here shows how optical stimulation of a relatively small group of mostly excitatory somatosensory neurons in the nonhuman primate brain is sufficient for eliciting a useful sensation from data acquired by simultaneous electrophysiology and from behavioral metrics. In this first report to date on optically neuromodulated behavior in the somatosensory cortex of nonhuman primates we do not yet dissect the details of the sensation the animals exerience or contrast it to those evoked by electrical stimulation, issues of considerable future interest.

  4. Long-Term Two-Photon Calcium Imaging of Neuronal Populations with Subcellular Resolution in Adult Non-human Primates.

    PubMed

    Sadakane, Osamu; Masamizu, Yoshito; Watakabe, Akiya; Terada, Shin-Ichiro; Ohtsuka, Masanari; Takaji, Masafumi; Mizukami, Hiroaki; Ozawa, Keiya; Kawasaki, Hiroshi; Matsuzaki, Masanori; Yamamori, Tetsuo

    2015-12-01

    Two-photon imaging with genetically encoded calcium indicators (GECIs) enables long-term observation of neuronal activity in vivo. However, there are very few studies of GECIs in primates. Here, we report a method for long-term imaging of a GECI, GCaMP6f, expressed from adeno-associated virus vectors in cortical neurons of the adult common marmoset (Callithrix jacchus), a small New World primate. We used a tetracycline-inducible expression system to robustly amplify neuronal GCaMP6f expression and up- and downregulate it for more than 100 days. We succeeded in monitoring spontaneous activity not only from hundreds of neurons three-dimensionally distributed in layers 2 and 3 but also from single dendrites and axons in layer 1. Furthermore, we detected selective activities from somata, dendrites, and axons in the somatosensory cortex responding to specific tactile stimuli. Our results provide a way to investigate the organization and plasticity of cortical microcircuits at subcellular resolution in non-human primates.

  5. Sources of variation in hair cortisol in wild and captive non-human primates.

    PubMed

    Fourie, Nicolaas H; Brown, Janine L; Jolly, Clifford J; Phillips-Conroy, Jane E; Rogers, Jeffrey; Bernstein, Robin M

    2016-04-01

    Hair cortisol analysis is a potentially powerful tool for evaluating adrenal function and chronic stress. However, the technique has only recently been applied widely to studies of wildlife, including primates, and there are numerous practical and technical factors that should be considered to ensure good quality data and the validity of results and conclusions. Here we report on various intrinsic and extrinsic sources of variation in hair cortisol measurements in wild and captive primates. Hair samples from both wild and captive primates revealed that age and sex can affect hair cortisol concentrations; these effects need to be controlled for when making comparisons between individual animals or populations. Hair growth rates also showed considerable inter-specific variation among a number of primate species. We describe technical limitations of hair analyses and variation in cortisol concentrations as a function of asynchronous hair growth, anatomical site of collection, and the amount and numbers of hair/s used for cortisol extraction. We discuss these sources of variation and their implications for proper study design and interpretation of results.

  6. Morphometric and Statistical Analysis of the Palmaris Longus Muscle in Human and Non-Human Primates

    PubMed Central

    Aversi-Ferreira, Roqueline A. G. M. F.; Bretas, Rafael Vieira; Maior, Rafael Souto; Davaasuren, Munkhzul; Paraguassú-Chaves, Carlos Alberto; Nishijo, Hisao; Aversi-Ferreira, Tales Alexandre

    2014-01-01

    The palmaris longus is considered a phylogenetic degenerate metacarpophalangeal joint flexor muscle in humans, a small vestigial forearm muscle; it is the most variable muscle in humans, showing variation in position, duplication, slips and could be reverted. It is frequently studied in papers about human anatomical variations in cadavers and in vivo, its variation has importance in medical clinic, surgery, radiological analysis, in studies about high-performance athletes, in genetics and anthropologic studies. Most studies about palmaris longus in humans are associated to frequency or case studies, but comparative anatomy in primates and comparative morphometry were not found in scientific literature. Comparative anatomy associated to morphometry of palmaris longus could explain the degeneration observed in this muscle in two of three of the great apes. Hypothetically, the comparison of the relative length of tendons and belly could indicate the pathway of the degeneration of this muscle, that is, the degeneration could be associated to increased tendon length and decreased belly from more primitive primates to those most derivate, that is, great apes to modern humans. In conclusion, in primates, the tendon of the palmaris longus increase from Lemuriformes to modern humans, that is, from arboreal to terrestrial primates and the muscle became weaker and tending to be missing. PMID:24860810

  7. Perception and description of New World non-human primates in the travel literature of the fifteenth and sixteenth centuries: a critical review.

    PubMed

    Veracini, Cecilia; Teixeira, Dante Martins

    2017-01-01

    The current work presents the results of a review of most of the European diaries and travel chronicles containing reports of New World non-human primates dating from the discovery of America in 1492 until the end of the sixteenth century. We report the integral texts translated into English of these literary sources, giving a critical interpretation from a historical and scientific point of view. We note the ways these primates were perceived and described, with attention to the most important characteristics that were highlighted by the first explorers. Ethnotaxonomy and vernacular names used to designate non-human primates are also provided. This new body of knowledge, based largely on empirical reports full of details and first-hand observations, emerged as the first nucleus in the natural history of Neotropical Primates.

  8. Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates.

    PubMed

    Lukashevich, Igor S; Carrion, Ricardo; Salvato, Maria S; Mansfield, Keith; Brasky, Kathleen; Zapata, Juan; Cairo, Cristiana; Goicochea, Marco; Hoosien, Gia E; Ticer, Anysha; Bryant, Joseph; Davis, Harry; Hammamieh, Rasha; Mayda, Maria; Jett, Marti; Patterson, Jean

    2008-09-26

    A single injection of ML29 reassortant vaccine for Lassa fever induces low, transient viremia, and low or moderate levels of ML29 replication in tissues of common marmosets depending on the dose of the vaccination. The vaccination elicits specific immune responses and completely protects marmosets against fatal disease by induction of sterilizing cell-mediated immunity. DNA array analysis of human peripheral blood mononuclear cells from healthy donors exposed to ML29 revealed that gene expression patterns in ML29-exposed PBMC and control, media-exposed PBMC, clustered together confirming safety profile of the ML29 in non-human primates. The ML29 reassortant is a promising vaccine candidate for Lassa fever.

  9. Diffeomorphic registration with self-adaptive spatial regularization for the segmentation of non-human primate brains.

    PubMed

    Risser, Laurent; Dolius, Lionel; Fonta, Caroline; Mescam, Muriel

    2014-01-01

    Cerebral aging has been linked to structural and functional changes in the brain throughout life. Here, we study the marmoset, a small non-human primate, in order to get insights into the mechanisms of brain aging in normal and pathological conditions. Imaging the brain of small animals with techniques such as MRI, quickly becomes a challenging task when compared with human brain imaging. Very often, a simple pre-processing step such as brain extraction cannot be achieved with classical tools. In this paper, we propose a diffeomorphic registration algorithm, which makes use of learned constraints to propagate the manual segmentation of a marmoset brain template to other MR images of marmoset brains. The main methological contribution of our paper is to explore a new strategy to automatically tune the spatial regularization of the deformations. Results show that we obtain a robust segmentation of the brain, even for images with a low contrast.

  10. Route and method of delivery of DNA vaccine influence immune responses in mice and non-human primates.

    PubMed Central

    McCluskie, M. J.; Brazolot Millan, C. L.; Gramzinski, R. A.; Robinson, H. L.; Santoro, J. C.; Fuller, J. T.; Widera, G.; Haynes, J. R.; Purcell, R. H.; Davis, H. L.

    1999-01-01

    BACKGROUND: In spite of the large number of studies that have evaluated DNA-based immunization, few have directly compared the immune responses generated by different routes of immunization, particularly in non-human primates. Here we examine the ability of a hepatitis B surface antigen (HBsAg)-encoding plasmid to induce immune responses in mice and non-human primates (rhesus monkeys: Macaca mulatta) after delivery by a number of routes. MATERIALS AND METHODS: Eight different injected [intraperitoneal (IP), intradermal (ID), intravenous (IV), intramuscular (IM), intraperineal (IPER), subcutaneous (SC), sublingual (SL), vaginal wall (VW)] and six noninjected [intranasal inhalation (INH), intranasal instillation (INS), intrarectal (IR), intravaginal (IVAG), ocular (Oc), oral feeding (oral)] routes and the gene gun (GG) were used to deliver HBsAg-expressing plasmid DNA to BALB/c mice. Sera were assessed for HBsAg-specific antibodies (anti-HBs, IgG, IgG1, IgG2a) and cytotoxic T lymphocyte (CTL) activity measured. Three of the most commonly used routes (IM, ID, GG) were compared in rhesus monkeys, also using HBsAg-expressing vectors. Monkeys were immunized with short (0-, 4- and 8-week) or long (0-, 12- and 24-week) intervals between boosts, and in the case of GG, also with different doses, and their sera were assessed for anti-HBs. RESULTS: In one study, anti-HBs were detected in plasma of mice treated by five of eight of the injected and none of the six noninjected routes. The highest levels of anti-HBs were induced by IM and IV injections, although significant titers were also obtained with SL and ID. Each of these routes also induced CTL, as did IPER and VW and one noninjected route (INH) that failed to induce antibodies. In a second study, GG (1.6 microg) was compared to ID and IM (100 microg) delivery. Significant titers were obtained by all routes after only one boost, with the highest levels detected by IM. Delivery to the skin by GG induced exclusively IgG1

  11. Non-human Primate Schlafen11 Inhibits Production of Both Host and Viral Proteins

    PubMed Central

    Stabell, Alex C.; Hawkins, John; Li, Manqing; Gao, Xia; David, Michael; Press, William H.; Sawyer, Sara L.

    2016-01-01

    Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is species-specific in its activity against HIV-1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species-specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified. PMID:28027315

  12. The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates

    PubMed Central

    Krivokrysenko, Vadim I.; Toshkov, Ilia A.; Gleiberman, Anatoli S.; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K.; Narizhneva, Natalya V.; Singh, Vijay K.; Whitnall, Mark H.; Purmal, Andrei A.; Shakhov, Alexander N.; Gudkov, Andrei V.; Feinstein, Elena

    2015-01-01

    There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1–48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40–60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters. PMID:26367124

  13. The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

    PubMed

    Krivokrysenko, Vadim I; Toshkov, Ilia A; Gleiberman, Anatoli S; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K; Narizhneva, Natalya V; Singh, Vijay K; Whitnall, Mark H; Purmal, Andrei A; Shakhov, Alexander N; Gudkov, Andrei V; Feinstein, Elena

    2015-01-01

    There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

  14. Home cage locomotor changes in non-human primates after prolonged welding-fume exposure.

    PubMed

    Kim, Choong Yong; Sung, Jae Hyuck; Chung, Yong Hyun; Park, Jung Duck; Han, Jeong Hee; Lee, Jong Seong; Heo, Jeong Doo; Yu, Il Je

    2013-12-01

    To define the relationship between the brain concentration of manganese and neurological signs, such as locomotion, after prolonged welding-fume exposure, cynomolgus monkeys were acclimated for 1 month and then divided into three concentration groups: unexposed, low concentration (31 mg/m(3) total suspended particulate (TSP), 0.9 mg/m(3) of Mn), and high concentration (62 mg/m(3) TSP, 1.95 mg/m(3) of Mn) of TSP. The monkeys were exposed to manual metal-arc stainless steel (MMA-SS) welding fumes for 2 h per day over 8 months in an inhalation chamber system equipped with an automatic fume generator. The home cage locomotor activity and patterns were determined using a camera system over 2-4 consecutive days. After 25 and 32 weeks of exposure, the home cage locomotor activity of the high-concentration primates was found to be 5-6 times higher than that of the unexposed primates, and this increased locomotor activity was maintained for 7 weeks after ceasing the welding-fume exposure, eventually subsiding to three times higher after 13 weeks of recovery. Therefore, the present results, along with our previous observations of a high magnetic resonance imaging (MRI) T1 signal in the globus pallidus and increased blood Mn concentration, indicate that prolonged welding-fume exposure can cause neurobehavioral changes in cynomolgus monkeys.

  15. The 'other faunivory' revisited: Insectivory in human and non-human primates and the evolution of human diet.

    PubMed

    McGrew, William C

    2014-06-01

    The role of invertebrates in the evolution of human diet has been under-studied by comparison with vertebrates and plants. This persists despite substantial knowledge of the importance of the 'other faunivory', especially insect-eating, in the daily lives of non-human primates and traditional human societies, especially hunters and gatherers. Most primates concentrate on two phyla, Mollusca and Arthropoda, but of the latter's classes, insects (especially five orders: Coleoptera, Hymenoptera, Isoptera, Lepidoptera, Orthoptera) are paramount. An insect product, bees' honey, is particularly important, and its collection shows a reversal of the usual sexual division of labor. Human entomophagy involves advanced technology (fire, containers) and sometimes domestication. Insectivory provides comparable calorific and nutritional benefits to carnivory, but with different costs. Much insectivory in hominoids entails elementary technology used in extractive foraging, such as termite fishing by chimpanzees. Elucidating insectivory in the fossil and paleontological record is challenging, but at least nine avenues are available: remains, lithics, residues, DNA, coprolites, dental microwear, stable isotopes, osteology, and depictions. All are in play, but some have been more successful so far than others.

  16. Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates.

    PubMed

    Kotterman, M A; Yin, L; Strazzeri, J M; Flannery, J G; Merigan, W H; Schaffer, D V

    2015-02-01

    Gene delivery vectors based on adeno-associated viruses (AAV) have exhibited promise in both preclinical disease models and human clinical trials for numerous disease targets, including the retinal degenerative disorders Leber's congenital amaurosis and choroideremia. One general challenge for AAV is that preexisting immunity, as well as subsequent development of immunity following vector administration, can severely inhibit systemic AAV vector gene delivery. However, the role of neutralizing antibodies (NABs) in AAV transduction of tissues considered to be immune privileged, such as the eye, is unclear in large animals. Intravitreal AAV administration allows for broad retinal delivery, but is more susceptible to interactions with the immune system than subretinal administration. To assess the effects of systemic anti-AAV antibody levels on intravitreal gene delivery, we quantified the anti-AAV antibodies present in sera from non-human primates before and after intravitreal injections with various AAV capsids. Analysis showed that intravitreal administration resulted in an increase in anti-AAV antibodies regardless of the capsid serotype, transgene or dosage of virus injected. For monkeys injected with wild-type AAV2 and/or an AAV2 mutant, the variable that most significantly affected the production of anti-AAV2 antibodies was the amount of virus delivered. In addition, post-injection antibody titers were highest against the serotype administered, but the antibodies were also cross-reactive against other AAV serotypes. Furthermore, NAB levels in serum correlated with those in vitreal fluid, demonstrating both that this route of administration exposes AAV capsid epitopes to the adaptive immune system and that serum measurements are predictive of vitreous fluid NAB titers. Moreover, the presence of preexisting NAB titers in the serum of monkeys correlated strongly (R=0.76) with weak, decaying or no transgene expression following intravitreal administration of AAV

  17. Induction of endometriosis alters the peripheral and endometrial regulatory T cell population in the non-human primate

    PubMed Central

    Braundmeier, A.; Jackson, K.; Hastings, J.; Koehler, J.; Nowak, R.; Fazleabas, A.

    2012-01-01

    BACKGROUND Endometriosis is a gynecological condition that is characterized by extreme abdominal pain and also decreased fertility. Regulatory T cells (Tregs) have immunosuppressive activity critical for embryonic implantation and likewise the acceptance of tissue engraftment. Utilizing the induced non-human primate (Papio anubis) model of endometriosis, we hypothesize that endometriosis decreases the peripheral and endomet rial Treg profile, whereas ectopic lesions have increased Treg localization. METHODS Peripheral blood and endometrium were obtained throughout the menstrual cycle prior to and after induction of disease. Animals were randomly assigned to control (n = 7) or diseased (n = 16) treatment groups. Endometriosis was induced by i.p. injection of autologous menstrual tissue for 2 consecutive months during menses. Peripheral blood and endometrial tissue were collected at d9-11PO at 1, 3, 6, 9, 12 and 15 months post-induction of disease for fluorescence-activated cell sorting, quantitative RT–PCR and immunohistochemistry. Ectopic lesions were excised at 1 and 6 months post-inoculation and also harvested at necropsy (15 months) and processed for RNA of IHC. Identification of Tregs through analysis of FOXP3 expression was conducted utlilizing several methodologies. Differences were determined by non-parametric statistical analysis between all treatment groups and time points. RESULTS In control animals, the proportion of peripheral natural Tregs (nTregs) was reduced (P < 0.05) during the mid- and late secretory stages of the menstrual cycle compared with menses. The induction of disease decreased peripheral Treg expression at early time points (P < 0.05) and this remained low throughout the time course, compared with the pre-inoculatory level of an individual. FOXP3 gene expression and Treg populations were also decreased in the eutopic endometrium (P < 0.05) compared with control animals, whereas these parameters were increased in ectopic lesions (P < 0

  18. Grooming-at-a-distance by exchanging calls in non-human primates

    PubMed Central

    Arlet, Malgorzata; Jubin, Ronan; Masataka, Nobuo; Lemasson, Alban

    2015-01-01

    The ‘social bonding hypothesis' predicts that, in large social groups, functions of gestural grooming should be partially transferred to vocal interactions. Hence, vocal exchanges would have evolved in primates to play the role of grooming-at-a-distance in order to facilitate the maintenance of social cohesion. However, there are few empirical studies testing this hypothesis. To address this point, we compared the rate of contact call exchanges between females in two captive groups of Japanese macaques as a function of female age, dominance rank, genetic relatedness and social affinity measured by spatial proximity and grooming interactions. We found a significant positive relationship between the time spent on grooming by two females and the frequency with which they exchanged calls. Our results conform to the predictions of the social bonding hypothesis, i.e. vocal exchanges can be interpreted as grooming-at-a-distance. PMID:26510675

  19. Effects of Caloric Restriction on Cardiovascular Aging in Non-human Primates and Humans

    PubMed Central

    Cruzen, Christina; Colman, Ricki J.

    2009-01-01

    Synopsis Approximately one in three Americans has some form of cardiovascular disease (CVD), accounting for one of every 2.8 deaths in the United States in 2004. Two of the major risk factors for CVD are advancing age and obesity. An intervention able to positively impact both aging and obesity, such as caloric restriction (CR), may prove extremely useful in the fight against CVD. CR is the only environmental or lifestyle intervention that has repeatedly been shown to increase maximum life span and to retard aging in laboratory rodents. In this article, we review evidence that CR in nonhuman primates and humans has a positive effect on risk factors for CVD. PMID:19944270

  20. Neuroendocrine control in social relationships in non-human primates: Field based evidence.

    PubMed

    Ziegler, Toni E; Crockford, Catherine

    2017-03-11

    Primates maintain a variety of social relationships and these can have fitness consequences. Research has established that different types of social relationships are unpinned by different or interacting hormonal systems, for example, the neuropeptide oxytocin influences social bonding, the steroid hormone testosterone influences dominance relationships, and paternal care is characterized by high oxytocin and low testosterone. Although the oxytocinergic system influences social bonding, it can support different types of social bonds in different species, whether pair bonds, parent-offspring bonds or friendships. It seems that selection processes shape social and mating systems and their interactions with neuroendocrine pathways. Within species, there are individual differences in the development of the neuroendocrine system: the social environment individuals are exposed to during ontogeny alters their neuroendocrine and socio-cognitive development, and later, their social interactions as adults. Within individuals, neuroendocrine systems can also have short-term effects, impacting on social interactions, such as those during hunting, intergroup encounters or food sharing, or the likelihood of cooperating, winning or losing. To understand these highly dynamic processes, extending research beyond animals in laboratory settings to wild animals living within their natural social and ecological setting may bring insights that are otherwise unreachable. Field endocrinology with neuropeptides is still emerging. We review the current status of this research, informed by laboratory studies, and identify questions particularly suited to future field studies. We focus on primate social relationships, specifically social bonds (mother-offspring, father-offspring, cooperative breeders, pair bonds and adult platonic friendships), dominance, cooperation and in-group/out-group relationships, and examine evidence with respect to the 'tend and defend' hypothesis.

  1. Increases in Endogenous or Exogenous Progestins Promote Virus-Target Cell Interactions within the Non-human Primate Female Reproductive Tract

    PubMed Central

    Carias, Ann M.; Fought, Angela J.; Kotnik Halavaty, Katarina; Anderson, Meegan R.; Jimenez, Maria L.; McRaven, Michael D.; Gioia, Casey J.; Henning, Tara R.; Smith, James M.; Pereira, Lara E.; Butler, Katherine; McNicholl, S. Janet M.; Hendry, R. Michael; Hope, Thomas J.

    2016-01-01

    Currently, there are mounting data suggesting that HIV-1 acquisition in women can be affected by the use of certain hormonal contraceptives. However, in non-human primate models, endogenous or exogenous progestin-dominant states are shown to increase acquisition. To gain mechanistic insights into this increased acquisition, we studied how mucosal barrier function and CD4+ T-cell and CD68+ macrophage density and localization changed in the presence of natural progestins or after injection with high-dose DMPA. The presence of natural or injected progestins increased virus penetration of the columnar epithelium and the infiltration of susceptible cells into a thinned squamous epithelium of the vaginal vault, increasing the likelihood of potential virus interactions with target cells. These data suggest that increasing either endogenous or exogenous progestin can alter female reproductive tract barrier properties and provide plausible mechanisms for increased HIV-1 acquisition risk in the presence of increased progestin levels. PMID:27658293

  2. The importance of surface-based cues for face discrimination in non-human primates

    PubMed Central

    Parr, Lisa A.; Taubert, Jessica

    2011-01-01

    Understanding how individual identity is processed from faces remains a complex problem. Contrast reversal, showing faces in photographic negative, impairs face recognition in humans and demonstrates the importance of surface-based information (shading and pigmentation) in face recognition. We tested the importance of contrast information for face encoding in chimpanzees and rhesus monkeys using a computerized face-matching task. Results showed that contrast reversal (positive to negative) selectively impaired face processing in these two species, although the impairment was greater for chimpanzees. Unlike chimpanzees, however, monkeys performed just as well matching negative to positive faces, suggesting that they retained some ability to extract identity information from negative faces. A control task showed that chimpanzees, but not rhesus monkeys, performed significantly better matching face parts compared with whole faces after a contrast reversal, suggesting that contrast reversal acts selectively on face processing, rather than general visual-processing mechanisms. These results confirm the importance of surface-based cues for face processing in chimpanzees and humans, while the results were less salient for rhesus monkeys. These findings make a significant contribution to understanding the evolution of cognitive specializations for face processing among primates, and suggest potential differences between monkeys and apes. PMID:21123266

  3. Cultural evolution of systematically structured behaviour in a non-human primate

    PubMed Central

    Claidière, Nicolas; Smith, Kenny; Kirby, Simon; Fagot, Joël

    2014-01-01

    Culture pervades human life and is at the origin of the success of our species. A wide range of other animals have culture too, but often in a limited form that does not complexify through the gradual accumulation of innovations. We developed a new paradigm to study cultural evolution in primates in order to better evaluate our closest relatives' cultural capacities. Previous studies using transmission chain experimental paradigms, in which the behavioural output of one individual becomes the target behaviour for the next individual in the chain, show that cultural transmission can lead to the progressive emergence of systematically structured behaviours in humans. Inspired by this work, we combined a pattern reproduction task on touch screens with an iterated learning procedure to develop transmission chains of baboons (Papio papio). Using this procedure, we show that baboons can exhibit three fundamental aspects of human cultural evolution: a progressive increase in performance, the emergence of systematic structure and the presence of lineage specificity. Our results shed new light on human uniqueness: we share with our closest relatives essential capacities to produce human-like cultural evolution. PMID:25377450

  4. Cultural evolution of systematically structured behaviour in a non-human primate.

    PubMed

    Claidière, Nicolas; Smith, Kenny; Kirby, Simon; Fagot, Joël

    2014-12-22

    Culture pervades human life and is at the origin of the success of our species. A wide range of other animals have culture too, but often in a limited form that does not complexify through the gradual accumulation of innovations. We developed a new paradigm to study cultural evolution in primates in order to better evaluate our closest relatives' cultural capacities. Previous studies using transmission chain experimental paradigms, in which the behavioural output of one individual becomes the target behaviour for the next individual in the chain, show that cultural transmission can lead to the progressive emergence of systematically structured behaviours in humans. Inspired by this work, we combined a pattern reproduction task on touch screens with an iterated learning procedure to develop transmission chains of baboons (Papio papio). Using this procedure, we show that baboons can exhibit three fundamental aspects of human cultural evolution: a progressive increase in performance, the emergence of systematic structure and the presence of lineage specificity. Our results shed new light on human uniqueness: we share with our closest relatives essential capacities to produce human-like cultural evolution.

  5. Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates.

    PubMed

    Perreault, Mylène; Feng, Guo; Will, Sarah; Gareski, Tiffany; Kubasiak, David; Marquette, Kimberly; Vugmeyster, Yulia; Unger, Thaddeus J; Jones, Juli; Qadri, Ariful; Hahm, Seung; Sun, Ying; Rohde, Cynthia M; Zwijnenberg, Raphael; Paulsen, Janet; Gimeno, Ruth E

    2013-01-01

    Strong genetic data link the Tyrosine kinase receptor B (TrkB) and its major endogenous ligand brain-derived neurotrophic factor (BDNF) to the regulation of energy homeostasis, with loss-of-function mutations in either gene causing severe obesity in both mice and humans. It has previously been reported that peripheral administration of the endogenous TrkB agonist ligand neurotrophin-4 (NT-4) profoundly decreases food intake and body weight in rodents, while paradoxically increasing these same parameters in monkeys. We generated a humanized TrkB agonist antibody, TAM-163, and characterized its therapeutic potential in several models of type 2 diabetes and obesity. In vitro, TAM-163 bound to human and rodent TrkB with high affinity, activated all aspects of the TrkB signaling cascade and induced TrkB internalization and degradation in a manner similar to BDNF. In vivo, peripheral administration of TAM-163 decreased food intake and/or body weight in mice, rats, hamsters, and dogs, but increased food intake and body weight in monkeys. The magnitude of weight change was similar in rodents and non-human primates, occurred at doses where there was no appreciable penetration into deep structures of the brain, and could not be explained by differences in exposures between species. Rather, peripherally administered TAM-163 localized to areas in the hypothalamus and the brain stem located outside the blood-brain barrier in a similar manner between rodents and non-human primates, suggesting differences in neuroanatomy across species. Our data demonstrate that a TrkB agonist antibody, administered peripherally, causes species-dependent effects on body weight similar to the endogenous TrkB ligand NT-4. The possible clinical utility of TrkB agonism in treating weight regulatory disorder, such as obesity or cachexia, will require evaluation in man.

  6. Infrared neural stimulation of primary visual cortex in non-human primates

    PubMed Central

    Cayce, Jonathan M.; Friedman, Robert M.; Chen, Gang; Jansen, E. Duco; Mahadevan-Jansen, Anita; Roe, Anna W.

    2014-01-01

    Infrared neural stimulation (INS) is an alternative neurostimulation modality that uses pulsed infrared light to evoke spatially precise neural activity that does not require direct contact with neural tissue. With these advantages INS has the potential to increase our understanding of specific neural pathways and impact current diagnostic and therapeutic clinical applications. In order to develop this technique, we investigate the feasibility of INS (λ = 1.875 μm, fiber diameter = 100–400 μm) to activate and modulate neural activity in primary visual cortex (V1) of Macaque monkeys. Infrared neural stimulation was found to evoke localized neural responses as evidenced by both electrophysiology and intrinsic signal optical imaging (OIS). Single unit recordings acquired during INS indicated statistically significant increases in neuron firing rates that demonstrate INS evoked excitatory neural activity. Consistent with this, INS stimulation led to focal intensity-dependent reflectance changes recorded with OIS. We also asked whether INS is capable of stimulating functionally specific domains in visual cortex and of modulating visually evoked activity in visual cortex. We found that application of INS via 100 μm or 200 μm fiber optics produced enhancement of visually evoked OIS response confined to the eye column where INS was applied and relative suppression of the other eye column. Stimulating the cortex with a 400 μm fiber, exceeding the ocular dominance width, led to relative suppression, consistent with involvement of inhibitory surrounds. This study is the first to demonstrate that INS can be used to either enhance or diminish visual cortical response and that this can be done in a functional domain specific manner. INS thus holds great potential for use as a safe, non-contact, focally specific brain stimulation technology in primate brains. PMID:23994125

  7. A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates

    PubMed Central

    Hjorth, Stephan; Karlsson, Cecilia; Jucaite, Aurelija; Varnäs, Katarina; Hamrén, Ulrika Wählby; Johnström, Peter; Gulyás, Balázs; Donohue, Sean R; Pike, Victor W; Halldin, Christer; Farde, Lars

    2015-01-01

    There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization. Thus, as part of a compound differentiation effort, three novel selective CB1 receptor (CB1R) antagonists, developed by AstraZeneca (AZ) for the treatment of obesity, were compared with two clinically tested reference compounds, rimonabant and taranabant, with regard to receptor occupancy relative to dose and exposure. A total of 42 PET measurements were performed in 6 non-human primates using the novel CB1R antagonist radioligand [11C]SD5024. The AZ CB1R antagonists bound in a saturable manner to brain CB1R with in vivo affinities similar to that of rimonabant and taranabant, compounds with proven weight loss efficacy in clinical trials. Interestingly, it was found that exposures corresponding to those needed for optimal clinical efficacy of rimonabant and taranabant resulted in a CB1R occupancy typically around ~20–30%, thus much lower than what would be expected for classical G-protein coupled receptor (GPCR) antagonists in other therapeutic contexts. These findings are also discussed in relation to emerging literature on the potential usefulness of ‘neutral’ vs. ‘classical’ CB1R (inverse agonist) antagonists. The study additionally highlighted the usefulness of the radioligand [11C]SD5024 as a specific tracer for CB1R in the primate brain, though an arterial input function would ideally be required in future studies to further assure accurate quantitative analysis of specific binding. PMID:25791528

  8. A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.

    PubMed

    Hjorth, Stephan; Karlsson, Cecilia; Jucaite, Aurelija; Varnäs, Katarina; Wählby Hamrén, Ulrika; Johnström, Peter; Gulyás, Balázs; Donohue, Sean R; Pike, Victor W; Halldin, Christer; Farde, Lars

    2016-02-01

    There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization. Thus, as part of a compound differentiation effort, three novel selective CB1 receptor (CB1R) antagonists, developed by AstraZeneca (AZ) for the treatment of obesity, were compared with two clinically tested reference compounds, rimonabant and taranabant, with regard to receptor occupancy relative to dose and exposure. A total of 42 PET measurements were performed in 6 non-human primates using the novel CB1R antagonist radioligand [(11)C]SD5024. The AZ CB1R antagonists bound in a saturable manner to brain CB1R with in vivo affinities similar to that of rimonabant and taranabant, compounds with proven weight loss efficacy in clinical trials. Interestingly, it was found that exposures corresponding to those needed for optimal clinical efficacy of rimonabant and taranabant resulted in a CB1R occupancy typically around ∼20-30%, thus much lower than what would be expected for classical G-protein coupled receptor (GPCR) antagonists in other therapeutic contexts. These findings are also discussed in relation to emerging literature on the potential usefulness of 'neutral' vs. 'classical' CB1R (inverse agonist) antagonists. The study additionally highlighted the usefulness of the radioligand [(11)C]SD5024 as a specific tracer for CB1R in the primate brain, though an arterial input function would ideally be required in future studies to further assure accurate quantitative analysis of specific binding.

  9. An implicit measure of olfactory performance for non-human primates reveals aversive and pleasant odor conditioning.

    PubMed

    Livneh, Uri; Paz, Rony

    2010-09-30

    We have little understanding of how odorants are processed in neural networks of the primate brain. Because chemo-stimuli are harder to control than physical stimuli (e.g. vision, audition), such research was limited by the temporal resolution, accuracy, and reliability of olfactometers (odor producing machines). Recent advances were able to create olfactometers that overcome these limitations, allowing their use together with neuroimaging techniques in humans. From the behavioral point of view, olfaction research requires a behavioral measure that can be used to quantify olfactory performance. This becomes a real problem when working with animals, where, unlike humans, explicit measures are harder to obtain. Furthermore, because odorants are powerful primitive reinforcers, such implicit measures can be beneficial to use in learning paradigms. Here we describe an olfactometer suitable for use in non-human primates, and an end-port design that allows the accurate measure of real-time respiratory modulations that are elicited in response to odor presentation. We demonstrate that this implicit measure is differentially modulated when experiencing pleasant or aversive odors. We then present an experimental paradigm in which monkeys learn to associate tones with odors, and show that the time delay from the conditioned stimuli to the next breath can be used to measure learning and memory expression in this paradigm. Using this construct, we reveal olfactory performance during acquisition and extinction of odor conditioning. These techniques can be used in electrophysiological recordings from relevant brain areas to shed light on neural networks involved in odor processing and reinforcement-learning.

  10. NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure.

    PubMed

    Halene, Tobias B; Kozlenkov, Alexey; Jiang, Yan; Mitchell, Amanda C; Javidfar, Behnam; Dincer, Aslihan; Park, Royce; Wiseman, Jennifer; Croxson, Paula L; Giannaris, Eustathia Lela; Hof, Patrick R; Roussos, Panos; Dracheva, Stella; Hemby, Scott E; Akbarian, Schahram

    2016-02-01

    Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6 months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.

  11. Could an experimental dengue virus infection fail to induce solid immunity against homologous viral challenge in non-human primates?

    PubMed

    Valdés, Iris; Gil, Lázaro; Lazo, Laura; Marcos, Ernesto; Martín, Jorge; Suzarte, Edith; Castro, Jorge; Romero, Yaremis; Guillén, Gerardo; Hermida, Lisset

    2016-02-01

    There are several dengue vaccine candidates at advanced stages of development, but none of them are licensed. Despite the reactogenicity and immunogenicity profile in humans of the tetravalent ChimeriVax™ dengue vaccine candidate, in efficacy trials, it has failed to confer complete protection against dengue virus (DENV)-1 and DENV-2. However, full protection against the four serotypes had been observed previously in monkeys immunized with this vaccine candidate. Some authors have tried to explain this contradiction by hypothesizing that protection rates in non-human primates (NHPs) are associated with a lack of post-challenge anamnestic immune responses. Here, we studied the protection and anamnestic response patterns after homologous challenge in NHPs previously infected with DENV-2. Two immunization schemes were used, varying the viral doses and the intervals between them. Animals developed immunity against DENV-2 that provided full protection against reinfection with a homologous virus. However, all monkeys showed a significant increase in antiviral and neutralizing antibody titers after challenge. Our results suggest that sterilizing immunity could not be induced by infection with the virus despite the lack of detectable viremia in some animals in which an increase in antibody titer was observed. For this reason, we propose that the lack of an anamnestic neutralizing antibody response after challenge, as suggested by some authors, should be carefully reviewed as a criterion for evaluating the functionality of vaccine candidates.

  12. Future of liver transplantation: non-human primates for patient-specific organs from induced pluripotent stem cells.

    PubMed

    Sanal, Madhusudana Girija

    2011-08-28

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient's genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly.

  13. Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

    NASA Astrophysics Data System (ADS)

    Downs, Matthew E.; Buch, Amanda; Karakatsani, Maria Eleni; Konofagou, Elisa E.; Ferrera, Vincent P.

    2015-10-01

    Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

  14. Isolation and maintenance of Balantidium coli (Malmsteim, 1857) cultured from fecal samples of pigs and non-human primates.

    PubMed

    Barbosa, Alynne da Silva; Bastos, Otilio Machado Pereira; Uchôa, Claudia M Antunes; Pissinatti, Alcides; Ferreira Filho, Paulo Ricardo; Dib, Lais Verdan; Azevedo, Eduarda Peixoto; de Siqueira, Mayara Perlingeiro; Cardozo, Matheus Lessa; Amendoeira, Maria Regina Reis

    2015-06-15

    Balantidium coli is a protozoa that can determine dysentery in humans, pigs and non-human primates having zoonotic potential. The lack of standardization in isolation and maintenance hinders the development of research on its biology and epidemiology. This study is aimed to standardize the isolation and maintenance of this parasite from animal feces, in culture medium, Pavlova modified. From 2012 to 2014, 1905 fecal samples were collected from captive animals of Rio de Janeiro. Were selected for isolation samples with a minimum of 10 trophozoites and/or 30 cysts of B. coli, totaling 88 pigs, 26 Cynomolgus and 90 rhesus macaques. In the presence of cysts, the sample was homogenized in saline solution, 500 μL was removed and inoculated into culture medium. The material that contained trophozoites the inoculum was made from 240 μL of fecal solution. All inoculate tubes with the subcultures were kept at 36°C, and sterile rice starch was always added to the medium. The parasites isolate from pigs, 34%, and from Cynomolgus 38.4% were maintained in vitro for a period of more than 24 months. These procedures proved to be adequate for isolation and maintenance of B. coli from different animals, they were found to be inexpensive and easy to perform.

  15. Manganese neurotoxicity: new perspectives from behavioral, neuroimaging, and neuropathological studies in humans and non-human primates

    PubMed Central

    Guilarte, Tomás R.

    2013-01-01

    Manganese (Mn) is an essential metal and has important physiological functions for human health. However, exposure to excess levels of Mn in occupational settings or from environmental sources has been associated with a neurological syndrome comprising cognitive deficits, neuropsychological abnormalities and parkinsonism. Historically, studies on the effects of Mn in humans and experimental animals have been concerned with effects on the basal ganglia and the dopaminergic system as it relates to movement abnormalities. However, emerging studies are beginning to provide significant evidence of Mn effects on cortical structures and cognitive function at lower levels than previously recognized. This review advances new knowledge of putative mechanisms by which exposure to excess levels of Mn alters neurobiological systems and produces neurological deficits not only in the basal ganglia but also in the cerebral cortex. The emerging evidence suggests that working memory is significantly affected by chronic Mn exposure and this may be mediated by alterations in brain structures associated with the working memory network including the caudate nucleus in the striatum, frontal cortex and parietal cortex. Dysregulation of the dopaminergic system may play an important role in both the movement abnormalities as well as the neuropsychiatric and cognitive function deficits that have been described in humans and non-human primates exposed to Mn. PMID:23805100

  16. Future of liver transplantation: Non-human primates for patient-specific organs from induced pluripotent stem cells

    PubMed Central

    Sanal, Madhusudana Girija

    2011-01-01

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient’s genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly. PMID:21990949

  17. Non-ABO blood group systems phenotyping in non-human primates for blood banking laboratory and xenotransplantation.

    PubMed

    Ramis, G; Martínez-Alarcon, L; Quereda, J J; Mrowiec, A; Funes, C; Ríos, A; Ramírez, P; Muñoz, A; Majado, M J

    2013-04-01

    Some biomedical research procedures, such as organ xenotransplantation, usually require intensive hemotherapy. Knowledge of the whole phenotype of blood donor and graft could be useful in the field of xenotransplantation. Human and simian-type categories of blood groups have been established and they can be tested by standard methods used for human blood grouping. The aim of this work was to study the incidence of non-ABO blood group systems in different species of non-human primates, which are employed in biomedical research. The phenotype of Rh, Lewis, Kidd, Kell, MNSs, Lutheran, P and Duffy antigens was investigated in olive baboon (n = 48), chacma baboon (n = 9), Guinea baboon (n = 14), Rhesus macaque (n = 38) and squirrel monkey (n = 30) by using commercial microtyping cards. Kell, Lutheran, Kidd and Duffy antigens have been detected in all species, Rh in squirrel monkey, MNSs in rhesus macaque and squirrel monkey, and Lewis in baboon and rhesus macaque. There were differences in frequency and haemagglutination scores between species regardless of their gender and age. The main differences were found in squirrel monkey when compared with baboons and macaques. This typing system provides a tool to assess the presence of antigens in animals used for experimental procedures, such as xenotransplantation and xenotransfusion.

  18. Scatter correction for large non-human primate brain imaging using microPET

    NASA Astrophysics Data System (ADS)

    Naidoo-Variawa, S.; Lehnert, W.; Banati, R. B.; Meikle, S. R.

    2011-04-01

    The baboon is well suited to pre-clinical evaluation of novel radioligands for positron emission tomography (PET). We have previously demonstrated the feasibility of using a high resolution animal PET scanner for this application in the baboon brain. However, the non-homogenous distribution of tissue density within the head may give rise to photon scattering effects that reduce contrast and compromise quantitative accuracy. In this study, we investigated the magnitude and distribution of scatter contributing to the final reconstructed image and its variability throughout the baboon brain using phantoms and Monte Carlo simulated data. The scatter fraction is measured up to 36% at the centre of the brain for a wide energy window (350-650 keV) and 19% for a narrow (450-650 keV) window. We observed less than 3% variation in the scatter fraction throughout the brain and found that scattered events arising from radioactivity outside the field of view contribute less than 1% of measured coincidences. In a contrast phantom, scatter and attenuation correction improved contrast recovery compared with attenuation correction on its own and reduced bias to less than 10% at the expense of the reduced signal-to-noise ratio. We conclude that scatter correction is a necessary step for ensuring high quality measurements of the radiotracer distribution in the baboon brain with a microPET scanner, while it is not necessary to model out of field of view scatter or a spatially variant scatter function.

  19. Sexually selected skin colour is heritable and related to fecundity in a non-human primate

    PubMed Central

    Dubuc, Constance; Winters, Sandra; Allen, William L.; Brent, Lauren J. N.; Cascio, Julie; Maestripieri, Dario; Ruiz-Lambides, Angelina V.; Widdig, Anja; Higham, James P.

    2014-01-01

    Sexual selection promotes the prevalence of heritable traits that increase an individual's reproductive rate. Despite theoretically strong directional selection, sexually selected traits can show inter-individual variation. Here, we investigate whether red skin ornamentation, a rare example of a male mammalian trait involved in mate attraction, influences fecundity and is heritable in rhesus macaques (Macaca mulatta), and explore the mechanisms that are involved in maintaining trait variation. Interestingly, the trait is expressed by and is attractive to both sexes. We collected facial images of 266 free-ranging individuals and modelled skin redness and darkness to rhesus macaque vision. We used 20 years of genetic parentage data to calculate selection gradients on the trait and perform heritability analyses. Results show that males who were both darkly coloured and high-ranking enjoyed higher fecundity. Female skin redness was positively linked to fecundity, although it remains unclear whether this influences male selectiveness. Heritability explained 10–15% of the variation in redness and darkness, and up to 30% for skin darkness when sexes are considered separately, suggesting sex-influenced inheritance. Our results suggest that inter-individual variation is maintained through condition-dependence, with an added effect of balancing selection on male skin darkness, providing rare evidence for a mammalian trait selected through inter-sexual selection. PMID:25253459

  20. Detection of modulated tones in modulated noise by non-human primates.

    PubMed

    Bohlen, Peter; Dylla, Margit; Timms, Courtney; Ramachandran, Ramnarayan

    2014-10-01

    In natural environments, many sounds are amplitude-modulated. Amplitude modulation is thought to be a signal that aids auditory object formation. A previous study of the detection of signals in noise found that when tones or noise were amplitude-modulated, the noise was a less effective masker, and detection thresholds for tones in noise were lowered. These results suggest that the detection of modulated signals in modulated noise would be enhanced. This paper describes the results of experiments investigating how detection is modified when both signal and noise were amplitude-modulated. Two monkeys (Macaca mulatta) were trained to detect amplitude-modulated tones in continuous, amplitude-modulated broadband noise. When the phase difference of otherwise similarly amplitude-modulated tones and noise were varied, detection thresholds were highest when the modulations were in phase and lowest when the modulations were anti-phase. When the depth of the modulation of tones or noise was varied, detection thresholds decreased if the modulations were anti-phase. When the modulations were in phase, increasing the depth of tone modulation caused an increase in tone detection thresholds, but increasing depth of noise modulations did not affect tone detection thresholds. Changing the modulation frequency of tone or noise caused changes in threshold that saturated at modulation frequencies higher than 20 Hz; thresholds decreased when the tone and noise modulations were in phase and decreased when they were anti-phase. The relationship between reaction times and tone level were not modified by manipulations to the nature of temporal variations in the signal or noise. The changes in behavioral threshold were consistent with a model where the brain subtracted noise from signal. These results suggest that the parameters of the modulation of signals and maskers heavily influence detection in very predictable ways. These results are consistent with some results in humans and avians

  1. Finding the beat: a neural perspective across humans and non-human primates

    PubMed Central

    Merchant, Hugo; Grahn, Jessica; Trainor, Laurel; Rohrmeier, Martin; Fitch, W. Tecumseh

    2015-01-01

    Humans possess an ability to perceive and synchronize movements to the beat in music (‘beat perception and synchronization’), and recent neuroscientific data have offered new insights into this beat-finding capacity at multiple neural levels. Here, we review and compare behavioural and neural data on temporal and sequential processing during beat perception and entrainment tasks in macaques (including direct neural recording and local field potential (LFP)) and humans (including fMRI, EEG and MEG). These abilities rest upon a distributed set of circuits that include the motor cortico-basal-ganglia–thalamo-cortical (mCBGT) circuit, where the supplementary motor cortex (SMA) and the putamen are critical cortical and subcortical nodes, respectively. In addition, a cortical loop between motor and auditory areas, connected through delta and beta oscillatory activity, is deeply involved in these behaviours, with motor regions providing the predictive timing needed for the perception of, and entrainment to, musical rhythms. The neural discharge rate and the LFP oscillatory activity in the gamma- and beta-bands in the putamen and SMA of monkeys are tuned to the duration of intervals produced during a beat synchronization–continuation task (SCT). Hence, the tempo during beat synchronization is represented by different interval-tuned cells that are activated depending on the produced interval. In addition, cells in these areas are tuned to the serial-order elements of the SCT. Thus, the underpinnings of beat synchronization are intrinsically linked to the dynamics of cell populations tuned for duration and serial order throughout the mCBGT. We suggest that a cross-species comparison of behaviours and the neural circuits supporting them sets the stage for a new generation of neurally grounded computational models for beat perception and synchronization. PMID:25646516

  2. Effect of palm olein oil in a moderate-fat diet on plasma lipoprotein profile and aortic atherosclerosis in non-human primates.

    PubMed

    van Jaarsveld, Paul J; Smuts, Cornelius M; Benadé, A Spinnler

    2002-01-01

    Several studies have reported on the effect of palm olein oil (PO; palmitic acid content approximately 38%) incorporation into the diet on blood cholesterol concentration. Information on the effect of PO on atherosclerosis is, however, lacking. In vervet monkeys (Cercopithecus aethiops), low-density lipoprotein cholesterol (LDL-C) concen-trations can be modulated by the type and amount of fat in the diet. The vervet is a proven model for both the type and composition of human atherosclerotic lesions. The aim of this study was to determine the effect of PO in a moderate-fat moderate-cholesterol diet (MFD) on plasma lipoproteins and the progression of atherosclerosis in a non-human primate model after 25.5 months of dietary exposure. Thirty adult male vervets, never exposed to a Western-type atherogenic diet, were stabilised on a MFD (28%E fat; 26 mg cholesterol/1000 kJ) with a polyunsaturated to saturated fatty acid (P/S) ratio of 0.4 for six weeks. Baseline LDL-C, high-density lipoprotein (HDL)-C and bodyweight were used to stratify the vervets into three comparable groups of 10 each. One group continued with the MFD in which 11.0%E was derived from lard (AF). In the other two groups, the AF was substituted isocalorically with either sunflower oil (SO) or PO. Plasma lipids were measured at 6-monthly intervals and atherosclerosis was assessed in the aorta and in five peripheral arteries after 25.5 months of dietary exposure. The frequency of atherosclerosis in peripheral arteries and aortas was low. PO, relative to SO and AF, significantly reduced the risk for developing early lesions in peripheral arteries (P = 0.0277 and P = 0.0038, respectively) and, relative to AF, in aortas (P = 0.0335). The cholesterolaemic effect of MFD-PO was not significantly different from MFD-SO and MFD-AF. However, at 24 months the plasma total cholesterol concentration with MFD-AF was significantly higher than with MFD-SO (P = 0.0256). It is confirmed that a MFD with PO is no different

  3. Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3

    PubMed Central

    Maekawa, Tomoki; Briones, Ruel A.; Resuello, Ranillo R.G.; Tuplano, Joel V.; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro; Koutsogiannaki, Sophia; Garcia, Cristina A.G.; Ricklin, Daniel; Lambris, John D.; Hajishengallis, George

    2016-01-01

    Aim Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. We assessed whether the C3 inhibitor Cp40 inhibits naturally-occurring periodontitis in non-human primates. Materials and Methods Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for six weeks followed by a 6-week follow-up period. Clinical periodontal examinations and collection of gingival crevicular fluid and biopsies of gingiva and bone were performed at baseline and during the study. A one-way repeated measures ANOVA was used for data analysis. Results Whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least six weeks following drug discontinuation. Conclusion Cp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in non-human primates, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis. PMID:26728318

  4. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species

    PubMed Central

    Johnston, Miles; Zakharov, Andrei; Papaiconomou, Christina; Salmasi, Giselle; Armstrong, Dianna

    2004-01-01

    Background The parenchyma of the brain does not contain lymphatics. Consequently, it has been assumed that arachnoid projections into the cranial venous system are responsible for cerebrospinal fluid (CSF) absorption. However, recent quantitative and qualitative evidence in sheep suggest that nasal lymphatics have the major role in CSF transport. Nonetheless, the applicability of this concept to other species, especially to humans has never been clarified. The purpose of this study was to compare the CSF and nasal lymph associations in human and non-human primates with those observed in other mammalian species. Methods Studies were performed in sheep, pigs, rabbits, rats, mice, monkeys and humans. Immediately after sacrifice (or up to 7 hours after death in humans), yellow Microfil was injected into the CSF compartment. The heads were cut in a sagittal plane. Results In the seven species examined, Microfil was observed primarily in the subarachnoid space around the olfactory bulbs and cribriform plate. The contrast agent followed the olfactory nerves and entered extensive lymphatic networks in the submucosa associated with the olfactory and respiratory epithelium. This is the first direct evidence of the association between the CSF and nasal lymph compartments in humans. Conclusions The fact that the pattern of Microfil distribution was similar in all species tested, suggested that CSF absorption into nasal lymphatics is a characteristic feature of all mammals including humans. It is tempting to speculate that some disorders of the CSF system (hydrocephalus and idiopathic intracranial hypertension for example) may relate either directly or indirectly to a lymphatic CSF absorption deficit. PMID:15679948

  5. Demonstration of a setup for chronic optogenetic stimulation and recording across cortical areas in non-human primates

    NASA Astrophysics Data System (ADS)

    Yazdan-Shahmorad, Azadeh; Diaz-Botia, Camilo; Hanson, Tim; Ledochowitsch, Peter; Maharabiz, Michel M.; Sabes, Philip N.

    2015-03-01

    Although several studies have shown the feasibility of using optogenetics in non-human primates (NHP), reliable largescale chronic interfaces have not yet been reported for such studies in NHP. Here we introduce a chronic setup that permits repeated, daily optogenetic stimulation and large-scale recording from the same sites in NHP cortex. The setup combines optogenetics with a transparent artificial dura (AD) and high-density micro-electrocorticography (μECoG). To obtain expression across large areas of cortex, we infused AAV5-CamKIIa-C1V1-EYFP viral vector using an infusion technique based on convection-enhanced delivery (CED) in primary somatosensory (S1) and motor (M1) cortices. By epifluorescent imaging through AD we were able to confirm high levels of expression covering about 110 mm2 of S1 and M1. We then incorporated a 192-channel μECoG array spanning 192 mm2 into the AD for simultaneous electrophysiological recording during optical stimulation. The array consists of patterned Pt-Au-Pt metal traces embedded in ~10 μm Parylene-C insulator. The parylene is sufficiently transparent to allow minimally attenuated optical access for optogenetic stimulation. The array was chronically implanted over the opsin-expressing areas in M1 and S1 for over two weeks. Optical stimulation was delivered via a fiber optic placed on the surface of the AD. With this setup, we recorded reliable evoked activity following light stimulation at several locations. Similar responses were recorded across tens of days, however a decline in the light-evoked signal amplitude was observed during this period due to the growth of dural tissue over the array. These results show the feasibility of a chronic interface for combined largescale optogenetic stimulation and cortical recordings across days.

  6. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species.

    PubMed

    Johnston, Miles; Zakharov, Andrei; Papaiconomou, Christina; Salmasi, Giselle; Armstrong, Dianna

    2004-12-10

    BACKGROUND: The parenchyma of the brain does not contain lymphatics. Consequently, it has been assumed that arachnoid projections into the cranial venous system are responsible for cerebrospinal fluid (CSF) absorption. However, recent quantitative and qualitative evidence in sheep suggest that nasal lymphatics have the major role in CSF transport. Nonetheless, the applicability of this concept to other species, especially to humans has never been clarified. The purpose of this study was to compare the CSF and nasal lymph associations in human and non-human primates with those observed in other mammalian species. METHODS: Studies were performed in sheep, pigs, rabbits, rats, mice, monkeys and humans. Immediately after sacrifice (or up to 7 hours after death in humans), yellow Microfil was injected into the CSF compartment. The heads were cut in a sagittal plane. RESULTS: In the seven species examined, Microfil was observed primarily in the subarachnoid space around the olfactory bulbs and cribriform plate. The contrast agent followed the olfactory nerves and entered extensive lymphatic networks in the submucosa associated with the olfactory and respiratory epithelium. This is the first direct evidence of the association between the CSF and nasal lymph compartments in humans. CONCLUSIONS: The fact that the pattern of Microfil distribution was similar in all species tested, suggested that CSF absorption into nasal lymphatics is a characteristic feature of all mammals including humans. It is tempting to speculate that some disorders of the CSF system (hydrocephalus and idiopathic intracranial hypertension for example) may relate either directly or indirectly to a lymphatic CSF absorption deficit.

  7. Real-Time, Transcranial Monitoring of Safe Blood-Brain Barrier Opening in Non-Human Primates

    PubMed Central

    Wu, Shih-Ying; Tung, Yao-Sheng; Downs, Matthew; Wang, Shutao; Chen, Cherry; Ferrera, Vincent; Konofagou, Elisa E.

    2014-01-01

    The delivery of drugs to specific neural targets faces two fundamental problems: (1) most drugs do not cross the blood-brain barrier, and (2) those that do, spread to the entire brain. To date, there exists only one non-invasive methodology with the potential to solve these problems: selective blood-brain barrier (BBB) opening using micro-bubble enhanced focused ultrasound. We have recently developed a single-element 500-kHz spherical transducer ultrasound setup for targeted BBB opening in the non-human primate that does not require simultaneous MRI monitoring. So far, however, the targeting accuracy that can be achieved with this system has not been quantified systematically. In this paper, the accuracy of this system was tested by targeting caudate nucleus and putamen of the basal ganglia in two macaque monkeys. The average lateral targeting error of the system was ∼2.5 mm while the axial targeting error, i.e., along the ultrasound path, was ∼1.5 mm. We have also developed a real-time treatment monitoring technique based on cavitation spectral analysis. This technique also allowed for delineation of a safe and reliable acoustic parameter window for BBB opening. In summary, the targeting accuracy of the system was deemed to be suitable to reliably open the BBB in specific sub-structures of the basal ganglia even in the absence of MRI-based verification of opening volume and position. This establishes the method and the system as a potentially highly useful tool for brain drug delivery. PMID:24505248

  8. A Recommended Laparoscopic Procedure for Implantation of Microcapsules in the Peritoneal Cavity of Non-human Primates

    PubMed Central

    Qi, Meirigeng; Lacik, Igor; Kolláriková, Gabriela; Strand, Berit L; Formo, Kjetil; Wang, Yong; Marchese, Enza; Mendoza-Elias, Joshua E.; Kinzer, Katie P.; Gatti, Francesca; Paushter, Daniel; Patel, Sonny; Oberholzer, Jose

    2013-01-01

    Background The anatomical spatial distribution of microencapsulated islets transplanted into the peritoneal cavity of large animals remains a relatively unexplored area of study. In this study, we developed a new implantation approach using laparoscopy in order to avoid microcapsule amalgamation. This approach constitutes a clinically relevant method, which can be used to evaluate the distribution and in vivo biocompatibility of various types of transplanted microcapsules in the future. Materials and Methods Two healthy baboons were implanted intraperitoneally with microencapsulated islets through mini-laparotomy and observed at 76 days after implantation. Nine baboons underwent laparoscopic implantation of approximately 80,000 empty microcapsules. Microcapsule distribution was observed by laparoscopic camera during and after implantation at 1, 2, and 4 weeks. At each time point, microcapsules were retrieved and evaluated with brightfield microscopy and histological analysis. Results Mini-laparotomic implantation resulted in microcapusle aggregation in both baboons. In contrast, laparoscopic implantation resulted in even distribution of microcapsules throughout the peritoneum without sedimentation to the Douglas space in all animals. In 8 out of 9 animals, retrieved microcapsules were evenly distributed in the peritoneal cavity and presented with no pericapsular overgrowth and easily washed out during laparoscopic procedure. The one exception was attributed to microcapsule contamination with blood from the abdominal wall following trocar insertion. Conclusions Laparoscopic implantation of microcapsules in non-human primates can be successfully performed and prevents microcapsule aggregation. Given the current widespread clinical application of laparoscopy, we propose that this presented laparoscopy technique could be applied in future clinical trials of microencapsulated islet transplantation. PMID:21435661

  9. Serial Multifocal Electroretinograms during Long-term Elevation and Reduction of Intraocular Pressure in Non-human Primates

    PubMed Central

    Nork, T. Michael; Kim, Charlene B. Y.; Heatley, Gregg A.; Kaufman, Paul L.; Lucarelli, Mark J.; Levin, Leonard A.; Ver Hoeve, James N.

    2010-01-01

    The purpose of this study was to evaluate the relationship between elevations of intraocular pressure (IOP) and the multifocal electroretinogram (mfERG) in non-human primates. Experimental glaucoma was induced in 4 rhesus and 4 cynomolgus monkeys by laser trabecular meshwork destruction (LTD) in one eye. To evaluate the contribution of ganglion cells to mfERG changes, one monkey of each species had previously underwent unilateral optic nerve transection (ONT). After ≥ 44 weeks of elevation, the IOP was reduced by trabeculectomy in 2 non-transected animals. In the intact (non-transected) animals there was an increase in the amplitude of the early mfERG waveforms (N1 and P1) of the first order kernel (K1) throughout the period of IOP elevation in all of the rhesus, but not all of the cynomolgus monkeys. A species difference was also present as a decrease of the second order kernel, first slice (K2.1) in all of the cynomolgus monkeys but only in 1 of the rhesus monkeys (the 1 with the ONT). Similar IOP effects on the mfERG were seen in the ONT animals. Surgical lowering of IOP resulted in a return of the elevated K1 amplitudes to baseline levels. However, the depressed K2.1 RMS in the cynomolgus monkeys did not recover. These results demonstrate species-specific changes in cone-driven retinal function during periods of elevated IOP. These IOP-related effects can occur in the absence of retinal ganglion cells and may be reversible. PMID:20422254

  10. Jaw-Opening Reflex and Corticobulbar Motor Excitability Changes During Quiet Sleep in Non-Human Primates

    PubMed Central

    Yao, Dongyuan; Lavigne, Gilles J.; Lee, Jye-Chang; Adachi, Kazunori; Sessle, Barry J.

    2013-01-01

    Study Objective: To test the hypothesis that the reflex and corticobulbar motor excitability of jaw muscles is reduced during sleep. Design: Polysomnographic recordings in the electrophysiological study. Setting: University sleep research laboratories. Participants and Interventions: The reflex and corticobulbar motor excitability of jaw muscles was determined during the quiet awake state (QW) and quiet sleep (QS) in monkeys (n = 4). Measurements and Results: During QS sleep, compared to QW periods, both tongue stimulation-evoked jaw-opening reflex peak and root mean square amplitudes were significantly decreased with stimulations at 2-3.5 × thresholds (P < 0.001). The jaw-opening reflex latency during sleep was also significantly longer than during QW. Intracortical microstimulation (ICMS) within the cortical masticatory area induced rhythmic jaw movements at a stable threshold (≤ 60 μA) during QW; but during QS, ICMS failed to induce any rhythmic jaw movements at the maximum ICMS intensity used, although sustained jaw-opening movements were evoked at significantly increased threshold (P < 0.001) in one of the monkeys. Similarly, during QW, ICMS within face primary motor cortex induced orofacial twitches at a stable threshold (≤ 35 μA), but the ICMS thresholds were elevated during QS. Soon after the animal awoke, rhythmic jaw movements and orofacial twitches could be evoked at thresholds similar to those before QS. Conclusions: The results suggest that the excitability of reflex and corticobulbar-evoked activity in the jaw motor system is depressed during QS. Citation: Yao D; Lavigne GJ; Lee JC; Adachi K; Sessle BJ. Jaw-opening reflex and corticobulbar motor excitability changes during quiet sleep in non-human primates. SLEEP 2013;36(2):269-280. PMID:23372275

  11. Refinements in husbandry, care and common procedures for non-human primates: Ninth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement.

    PubMed

    Jennings, M; Prescott, M J; Buchanan-Smith, Hannah M; Gamble, Malcolm R; Gore, Mauvis; Hawkins, Penny; Hubrecht, Robert; Hudson, Shirley; Jennings, Maggy; Keeley, Joanne R; Morris, Keith; Morton, David B; Owen, Steve; Pearce, Peter C; Prescott, Mark J; Robb, David; Rumble, Rob J; Wolfensohn, Sarah; Buist, David

    2009-04-01

    Preface Whenever animals are used in research, minimizing pain and distress and promoting good welfare should be as important an objective as achieving the experimental results. This is important for humanitarian reasons, for good science, for economic reasons and in order to satisfy the broad legal principles in international legislation. It is possible to refine both husbandry and procedures to minimize suffering and improve welfare in a number of ways, and this can be greatly facilitated by ensuring that up-to-date information is readily available. The need to provide such information led the British Veterinary Association Animal Welfare Foundation (BVAAWF), the Fund for the Replacement of Animals in Medical Experiments (FRAME), the Royal Society for the Prevention of Cruelty to Animals (RSPCA) and the Universities Federation for Animal Welfare (UFAW) to establish a Joint Working Group on Refinement (JWGR) in the UK. The chair is Professor David Morton and the secretariat is provided by the RSPCA. This report is the ninth in the JWGR series. The RSPCA is opposed to the use of animals in experiments that cause pain, suffering, distress or lasting harm and together with FRAME has particular concerns about the continued use of non-human primates. The replacement of primate experiments is a primary goal for the RSPCA and FRAME. However, both organizations share with others in the Working Group, the common aim of replacing primate experiments wherever possible, reducing suffering and improving welfare while primate use continues. The reports of the refinement workshops are intended to help achieve these aims. This report produced by the British Veterinary Association Animal Welfare Foundation (BVAAWF)/Fund for the Replacement of Animals in Medical Experiments (FRAME)/Royal Society for the Prevention of Cruelty to Animals (RSPCA)/Universities Federation for Animal Welfare (UFAW) Joint Working Group on Refinement (JWGR) sets out practical guidance on refining the

  12. Prevalence of gastrointestinal parasites in captive non-human primates of twenty-four zoological gardens in China.

    PubMed

    Li, Mei; Zhao, Bo; Li, Bo; Wang, Qiang; Niu, Lili; Deng, Jiabo; Gu, Xiaobin; Peng, Xuerong; Wang, Tao; Yang, Guangyou

    2015-06-01

    Captive primates are susceptible to gastrointestinal (GIT) parasitic infections, which are often zoonotic and can contribute to morbidity and mortality. Fecal samples were examined by the means of direct smear, fecal flotation, fecal sedimentation, and fecal cultures. Of 26.51% (317/1196) of the captive primates were diagnosed gastrointestinal parasitic infections. Trichuris spp. were the most predominant in the primates, while Entamoeba spp. were the most prevalent in Old World monkeys (P < 0.05). These preliminary data will improve the management of captive primates and the safety of animal keepers and visitors.

  13. Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates.

    PubMed

    Broadbent, Andrew J; Santos, Celia P; Paskel, Myeisha; Matsuoka, Yumiko; Lu, Janine; Chen, Zhongying; Jin, Hong; Subbarao, Kanta

    2015-01-01

    The development of an H2N2 vaccine is a priority in pandemic preparedness planning. We previously showed that a single dose of a cold-adapted (ca) H2N2 live attenuated influenza vaccine (LAIV) based on the influenza A/Ann Arbor/6/60 (AA ca) virus was immunogenic and efficacious in mice and ferrets. However, in a Phase I clinical trial, viral replication was restricted and immunogenicity was poor. In this study, we compared the replication of four H2N2 LAIV candidate viruses, AA ca, A/Tecumseh/3/67 (TEC67 ca), and two variants of A/Japan/305/57 (JAP57 ca) in three non-human primate (NHP) species: African green monkeys (AGM), cynomolgus macaques (CM) and rhesus macaques (RM). One JAP57 ca virus had glutamine and glycine at HA amino acid positions 226 and 228 (Q-G) that binds to α2-3 linked sialic acids, and one had leucine and serine that binds to α2-3 and α2-6 linked residues (L-S). The replication of all ca viruses was restricted, with low titers detected in the upper respiratory tract of all NHP species, however replication was detected in significantly more CMs than AGMs. The JAP57 ca Q-G and TEC67 ca viruses replicated in a significantly higher percentage of NHPs than the AA ca virus, with the TEC67 ca virus recovered from the greatest percentage of animals. Altering the receptor specificity of the JAP57 ca virus from α2-3 to both α2-3 and α2-6 linked sialic acid residues did not significantly increase the number of animals infected or the titer to which the virus replicated. Taken together, our data show that in NHPs the AA ca virus more closely reflects the human experience than mice or ferret studies. We suggest that CMs and RMs may be the preferred species for evaluating H2N2 LAIV viruses, and the TEC67 ca virus may be the most promising H2N2 LAIV candidate for further evaluation.

  14. Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates

    PubMed Central

    Broadbent, Andrew J.; Santos, Celia P.; Paskel, Myeisha; Matsuoka, Yumiko; Lu, Janine; Chen, Zhongying; Jin, Hong; Subbarao, Kanta

    2014-01-01

    The development of an H2N2 vaccine is a priority in pandemic preparedness planning. We previously showed that a single dose of a cold-adapted (ca) H2N2 live attenuated influenza vaccine (LAIV) based on the influenza A/Ann Arbor/6/60 (AA ca) virus was immunogenic and efficacious in mice and ferrets. However, in a Phase I clinical trial, viral replication was restricted and immunogenicity was poor. In this study, we compared the replication of four H2N2 LAIV candidate viruses, AA ca, A/Tecumseh/3/67 (TEC67 ca), and two variants of A/Japan/305/57 (JAP57 ca) in three non-human primate (NHP) species: African green monkeys (AGM), cynomolgus macaques (CM) and rhesus macaques (RM). One JAP57 ca virus had glutamine and glycine at HA amino acid positions 226 and 228 (Q-G) that binds to α2-3 linked sialic acids, and one had leucine and serine that binds to α2-3 and α2-6 linked residues (L-S). The replication of all ca viruses was restricted, with low titers detected in the upper respiratory tract of all NHP species, however replication was detected in significantly more CMs than AGMs. The JAP57 ca Q-G and TEC67 ca viruses replicated in a significantly higher percentage of NHPs than the AA ca virus, with the TEC67 ca virus recovered from the greatest percentage of animals. Altering the receptor specificity of the JAP57 ca virus from α2-3 to both α2-3 and α2-6 linked sialic acid residues did not significantly increase the number of animals infected or the titer to which the virus replicated. Taken together, our data show that in NHPs the AA ca virus more closely reflects the human experience than mice or ferret studies. We suggest that CMs and RMs may be the preferred species for evaluating H2N2 LAIV viruses, and the TEC67 ca virus may be the most promising H2N2 LAIV candidate for further evaluation. PMID:25444799

  15. Learning at a distance II. Statistical learning of non-adjacent dependencies in a non-human primate.

    PubMed

    Newport, Elissa L; Hauser, Marc D; Spaepen, Geertrui; Aslin, Richard N

    2004-09-01

    among learners in the types of patterned regularities they can acquire. Such studies with tamarins open interesting questions about the perceptual and computational capacities of human learners that may be essential for language acquisition, and how they may differ from those of non-human primates.

  16. Modeling Olfactory Bulb Evolution through Primate Phylogeny

    PubMed Central

    Heritage, Steven

    2014-01-01

    Adaptive characterizations of primates have usually included a reduction in olfactory sensitivity. However, this inference of derivation and directionality assumes an ancestral state of olfaction, usually by comparison to a group of extant non-primate mammals. Thus, the accuracy of the inference depends on the assumed ancestral state. Here I present a phylogenetic model of continuous trait evolution that reconstructs olfactory bulb volumes for ancestral nodes of primates and mammal outgroups. Parent-daughter comparisons suggest that, relative to the ancestral euarchontan, the crown-primate node is plesiomorphic and that derived reduction in olfactory sensitivity is an attribute of the haplorhine lineage. The model also suggests a derived increase in olfactory sensitivity at the strepsirrhine node. This oppositional diversification of the strepsirrhine and haplorhine lineages from an intermediate and non-derived ancestor is inconsistent with a characterization of graded reduction through primate evolution. PMID:25426851

  17. Hypothalamic Expression of KISS1 and Gonadotropin Inhibitory Hormone Genes During the Menstrual Cycle of a Non-Human Primate1

    PubMed Central

    Smith, Jeremy T.; Shahab, Muhammad; Pereira, Alda; Pau, K.-Y. Francis; Clarke, Iain J.

    2010-01-01

    Kisspeptin, the product of the KISS1 gene, stimulates gonadotropin-releasing hormone (GnRH) secretion; gonadotropin inhibitory hormone (GnIH), encoded by the RF-amide-related peptide (RFRP) or NPVF gene, inhibits the reproductive axis. In sheep, kisspeptin neurons are found in the lateral preoptic area (POA) and the arcuate nucleus (ARC) and may be important for initiating the preovulatory GnRH/luteinizing hormone (LH) surge. GnIH cells are located in the ovine dorsomedial hypothalamic nucleus (DMN) and paraventricular nucleus (PVN), with similar distribution in the primate. KISS1 cells are found in the primate POA and ARC, but the function that kisspeptin and GnIH play in primates has not been elucidated. We examined KISS1 and NPVF mRNA throughout the menstrual cycle of a female primate, rhesus macaque (Macaca mulatta), using in situ hybridization. KISS1-expressing cells were found in the POA and ARC, and NPVF-expressing cells were located in the PVN/DMN. KISS1 expression in the caudal ARC and POA was higher in the late follicular phase of the cycle (just before the GnRH/LH surge) than in the luteal phase. NPVF expression was also higher in the late follicular phase. We ascertained whether kisspeptin and/or GnIH cells project to GnRH neurons in the primate. Close appositions of kisspeptin and GnIH fibers were found on GnRH neurons, with no change across the menstrual cycle. These data suggest a role for kisspeptin in the stimulation of GnRH cells before the preovulatory GnRH/LH surge in non-human primates. The role of GnIH is less clear, with paradoxical up-regulation of gene expression in the late follicular phase of the menstrual cycle. PMID:20574054

  18. Fecal Microbiomes of Non-Human Primates in Western Uganda Reveal Species-Specific Communities Largely Resistant to Habitat Perturbation

    PubMed Central

    McCORD, ALEIA I.; CHAPMAN, COLIN A.; WENY, GEOFFREY; TUMUKUNDE, ALEX; HYEROBA, DAVID; KLOTZ, KELLY; KOBLINGS, AVERY S.; MBORA, DAVID N.M.; CREGGER, MELISSA; WHITE, BRYAN A.; LEIGH, STEVEN R.; GOLDBERG, TONY L.

    2014-01-01

    Primate gastrointestinal microbial communities are becoming increasingly appreciated for their relevance to comparative medicine and conservation, but the factors that structure primate “microbiomes” remain controversial. This study examined a community of primates in Kibale National Park, Uganda, to assess the relative importance of host species and location in structuring gastrointestinal microbiomes. Fecal samples were collected from primates in intact forest and from primates in highly disturbed forest fragments. People and livestock living nearby were also included, as was a geographically distant population of related red colobus in Kenya. A culture-free microbial community fingerprinting technique was used to analyze fecal microbiomes from 124 individual red colobus (Procolobus rufomitratus), 100 individual black-and-white colobus (Colobus guereza), 111 individual red-tailed guenons (Cercopithecus ascanius), 578 human volunteers, and 364 domestic animals, including cattle (Bos indicus and B. indicus × B. taurus crosses), goats (Caprus hircus), sheep (Ovis aries), and pigs (Sus scrofa). Microbiomes sorted strongly by host species, and forest fragmentation did not alter this pattern. Microbiomes of Kenyan red colobus sorted distinctly from microbiomes of Ugandan red colobus, but microbiomes from these two red colobus populations clustered more closely with each other than with any other species. Microbiomes from red colobus and black-and-white colobus were more differentiated than would be predicted by the phylogenetic relatedness of these two species, perhaps reflecting heretofore underappreciated differences in digestive physiology between the species. Within Kibale, social group membership influenced intra-specific variation among microbiomes. However, intra-specific variation was higher among primates in forest fragments than among primates in intact forest, perhaps reflecting the physical separation of fragments. These results suggest that, in this

  19. AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates.

    PubMed

    Jeyanathan, Mangalakumari; Shao, Zhongqi; Yu, Xuefeng; Harkness, Robin; Jiang, Rong; Li, Junqiang; Xing, Zhou; Zhu, Tao

    2015-01-01

    Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen-specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application.

  20. Pulmonary administration of interferon Beta-1a-fc fusion protein in non-human primates using an immunoglobulin transport pathway.

    PubMed

    Vallee, Sebastien; Rakhe, Swapnil; Reidy, Thomas; Walker, Sandra; Lu, Qi; Sakorafas, Paul; Low, Susan; Bitonti, Alan

    2012-04-01

    Currently, products containing interferon beta (IFNβ) are injected either intramuscularly or subcutaneously. To avoid the necessity of injection, we developed a novel monomeric Fc fusion protein of IFNβ (IFNβFc) that is absorbed via an immunoglobulin transport system present in the upper and central airways upon administration of the drug as an inhaled aerosol. The systemic absorption of IFNβFc through the lung in non-human primates, at deposited doses of 1, 3, and 10 μg/kg, was compared to the absorption of a single 3 μg/kg dose of IFNβ-1a (Avonex®) subcutaneously administered. IFNβFc was well absorbed through the lung, displaying dose proportional increases in serum concentrations, and was biologically active, as shown by increases in plasma neopterin levels. The circulating half-life of IFNβFc was ∼3 times longer (∼30 h) than that of IFNβ-1a, (8-9 h). At approximately equimolar doses of IFNβFc (10 μg/kg) and IFNβ-1a (3 μg/kg), the stimulation of neopterin over background levels was approximately equivalent, demonstrating that the longer half-life of IFNβFc compensated for the lower relative specific antiviral activity of IFNβFc measured in vitro. In conclusion, IFNβFc was efficiently absorbed after pulmonary delivery in non-human primates, retained its biological activity, and may offer a convenient alternative to injectable IFNβ.

  1. Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection

    PubMed Central

    Burdine, Marie S.; Orr, Lisa; Mackintosh, Samuel G.; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J.

    2017-01-01

    Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure. PMID:28350824

  2. Immunogenicity in mice and non-human primates of the Group A Streptococcal J8 peptide vaccine candidate conjugated to CRM197.

    PubMed

    Caro-Aguilar, Ivette; Ottinger, Elizabeth; Hepler, Robert W; Nahas, Deborah D; Wu, Chengwei; Good, Michael F; Batzloff, Michael; Joyce, Joseph G; Heinrichs, Jon H; Skinner, Julie M

    2013-03-01

    Vaccine development for Group A streptococcal (GAS) infection has been extensively focused on the N-terminal hypervariable or the C-terminal conserved regions of the M protein, a major virulence factor of GAS. We evaluated the immunogenicity and functional activity of the conserved C-terminal peptide vaccine candidate, J8, conjugated to CRM197, in two mouse strains: C3H (H2(k)) and Balb/c (H2(d)), and in rhesus macaques. Mice were immunized with J8-CRM197 formulated with Amorphous Aluminum Hydroxyphosphate Sulfate Adjuvant (AAHSA), and non-human primates were immunized with J8-CRM197 formulated with AAHSA, ISCOMATRIX (TM) adjuvant, or AAHSA/ISCOMATRIX adjuvant. J8-CRM197 was immunogenic in mice from both H2(k) and H2(d) backgrounds, and the antibodies generated bound to the surface of four different GAS serotypes and had functional bacterial opsonic activity. Mice immunized with J8-CRM197/AAHSA demonstrated varying degrees of protection from lethal challenge. We also demonstrated that J8-CRM197 is immunogenic in non-human primates. Our data confirm the utility of J8 as a potential GAS vaccine candidate and demonstrate that CRM197 is an acceptable protein carrier for this peptide.

  3. Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.

    PubMed

    Byrum, Stephanie D; Burdine, Marie S; Orr, Lisa; Mackintosh, Samuel G; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J

    2017-01-01

    Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure.

  4. Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

    PubMed Central

    Downs, Matthew E.; Buch, Amanda; Sierra, Carlos; Karakatsani, Maria Eleni; Chen, Shangshang; Konofagou, Elisa E.; Ferrera, Vincent P.

    2015-01-01

    Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used. PMID:25945493

  5. Systematic evaluation of monoclonal antibodies and immunoassays for the detection of Interferon-γ and Interleukin-2 in old and new world non-human primates.

    PubMed

    Höglind, Ankie; Areström, Irene; Ehrnfelt, Cecilia; Masjedi, Khosro; Zuber, Bartek; Giavedoni, Luis; Ahlborg, Niklas

    2017-02-01

    Non-human primates (NHP) provide important animal models for studies on immune responses to infections and vaccines. When assessing cellular immunity in NHP, cytokines are almost exclusively analyzed utilizing cross-reactive anti-human antibodies. The functionality of antibodies has to be empirically established for each assay/application as well as NHP species. A rational approach was employed to identify monoclonal antibodies (mAb) cross-reactive with many NHP species. Panels of new and established mAbs against human Interferon (IFN)-γ and Interleukin (IL)-2 were assessed for reactivity with eukaryotically expressed recombinant IFN-γ and IL-2, respectively, from Old (rhesus, cynomolgus and pigtail macaques, African green monkey, sooty mangabey and baboon) and New World NHP (Ma's night monkey, squirrel monkey and common marmoset). Pan-reactive mAbs, recognizing cytokines from all NHP species, were further analyzed in capture assays and flow cytometry with NHP peripheral blood mononuclear cells (PBMC). Pan-reactive mAb pairs for IFN-γ well as IL-2 were identified and used in ELISA to measure IFN-γ and IL-2, respectively, in Old and New World NHP PBMC supernatants. The same mAb pairs displayed high functionality in ELISpot and FluoroSpot for the measurement of antigen-specific IFN-γ and IL-2 responses using cynomolgus PBMC. Functionality of pan-reactive mAbs in flow cytometry was also verified with cynomolgus PBMC. The development of well-defined immunoassays functional with a panel of NHP species facilitates improved analyses of cellular immunity and enables inclusion in multiplex cytokine assays intended for a variety of NHP.

  6. Nodular Worm Infections in Wild Non-human Primates and Humans Living in the Sebitoli Area (Kibale National Park, Uganda): Do High Spatial Proximity Favor Zoonotic Transmission?

    PubMed Central

    Cibot, Marie; Guillot, Jacques; Lafosse, Sophie; Bon, Céline; Seguya, Andrew; Krief, Sabrina

    2015-01-01

    Background Nodular Oesophagostomum genus nematodes are a major public health concern in some African regions because they can be lethal to humans. Their relatively high prevalence in people has been described in Uganda recently. While non-human primates also harbor Oesophagostomum spp., the epidemiology of this oesophagostomosis and the role of these animals as reservoirs of the infection in Eastern Africa are not yet well documented. Methodology/Principal Findings The present study aimed to investigate Oesophagostomum infection in terms of parasite species diversity, prevalence and load in three non-human primates (Pan troglodytes, Papio anubis, Colobus guereza) and humans living in close proximity in a forested area of Sebitoli, Kibale National Park (KNP), Uganda. The molecular phylogenetic analyses provided the first evidence that humans living in the Sebitoli area harbored O. stephanostomum, a common species in free-ranging chimpanzees. Chimpanzees were also infected by O. bifurcum, a common species described in human populations throughout Africa. The recently described Oesophagostomum sp. found in colobine monkeys and humans and which was absent from baboons in the neighboring site of Kanyawara in KNP (10 km from Sebitoli), was only found in baboons. Microscopic analyses revealed that the infection prevalence and parasite load in chimpanzees were significantly lower in Kanyawara than in Sebitoli, an area more impacted by human activities at its borders. Conclusions/Significance Three different Oesophagostomum species circulate in humans and non-human primates in the Sebitoli area and our results confirm the presence of a new genotype of Oesophagostomum recently described in Uganda. The high spatiotemporal overlap between humans and chimpanzees in the studied area coupled with the high infection prevalence among chimpanzees represent factors that could increase the risk of transmission for O. stephanostomum between the two primate species. Finally, the

  7. The Physiological Effect of Human Grooming on the Heart Rate and the Heart Rate Variability of Laboratory Non-Human Primates: A Pilot Study in Male Rhesus Monkeys

    PubMed Central

    Grandi, Laura Clara; Ishida, Hiroaki

    2015-01-01

    Grooming is a widespread, essential, and complex behavior with social and affiliative valence in the non-human primate world. Its impact at the autonomous nervous system level has been studied during allogrooming among monkeys living in a semi-naturalistic environment. For the first time, we investigated the effect of human grooming to monkey in a typical experimental situation inside laboratory. We analyzed the autonomic response of male monkeys groomed by a familiar human (experimenter), in terms of the heart rate (HR) and heart rate variability (HRV) at different body parts. We considered the HRV in both the time (SDNN, RMSSD, and RMSSD/SDNN) and the frequency domain (HF, LF, and LF/HF). For this purpose, we recorded the electrocardiogram of two male rhesus monkeys seated in a primate chair while the experimenter groomed their mouth, chest, or arm. We demonstrated that (1) the grooming carried out by a familiar human determined a decrement of the HR and an increment of the HRV; (2) there was a difference in relation to the groomed body part. In particular, during grooming the mouth the HRV was higher than during grooming the arm and the chest. Taken together, the results represent the first evidence that grooming carried out by a familiar human on experimental monkeys has the comparable positive physiological effect of allogrooming between conspecifics. Moreover, since the results underlined the positive modulation of both HR and HRV, the present study could be a starting point to improve the well-being of non-human primates in experimental condition by means of grooming by a familiar person. PMID:26664977

  8. Patterns of microRNA Expression in Non-Human Primate Cells Correlate with Neoplastic Development In Vitro

    PubMed Central

    Teferedegne, Belete; Murata, Haruhiko; Quiñones, Mariam; Peden, Keith; Lewis, Andrew M.

    2010-01-01

    MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression post-transcriptionally. They play a critical role in developmental and physiological processes and have been implicated in the pathogenesis of several diseases including cancer. To identify miRNA signatures associated with different stages of neoplastic development, we examined the expression profile of 776 primate miRNAs in VERO cells (a neoplastically transformed cell line being used for the manufacture of viral vaccines), progenitor primary African green monkey kidney (pAGMK) cells, and VERO cell derivatives: spontaneously immortalized, non-tumorigenic, low-passage VERO cells (10-87 LP); tumorigenic, high-passage VERO cells (10-87 HP); and a cell line (10-87 T) derived from a 10-87 HP cell tumor xenograft in athymic nude mice. When compared with pAGMK cells, the majority of miRNAs were expressed at lower levels in 10-87 LP, 10-87 HP, and 10-87 T cells. We identified 10 up-regulated miRNAs whose level of expression correlated with VERO cell evolution from a non-tumorigenic phenotype to a tumorigenic phenotype. The overexpression of miR-376a and the polycistronic cluster of miR-376a, miR-376b and miR-376c conferred phenotypic changes to the non-tumorigenic 10-87 LP cells that mimic the tumorigenic 10-87 HP cells. Thirty percent of miRNAs that were components of the identified miRNAs in our spontaneously transformed AGMK cell model are also dysregulated in a variety of human tumors. These results may prove to be relevant to the biology of neoplastic development. In addition, one or more of these miRNAs could be biomarkers for the expression of a tumorigenic phenotype. PMID:21203544

  9. Patterns of microRNA expression in non-human primate cells correlate with neoplastic development in vitro.

    PubMed

    Teferedegne, Belete; Murata, Haruhiko; Quiñones, Mariam; Peden, Keith; Lewis, Andrew M

    2010-12-22

    MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression post-transcriptionally. They play a critical role in developmental and physiological processes and have been implicated in the pathogenesis of several diseases including cancer. To identify miRNA signatures associated with different stages of neoplastic development, we examined the expression profile of 776 primate miRNAs in VERO cells (a neoplastically transformed cell line being used for the manufacture of viral vaccines), progenitor primary African green monkey kidney (pAGMK) cells, and VERO cell derivatives: spontaneously immortalized, non-tumorigenic, low-passage VERO cells (10-87 LP); tumorigenic, high-passage VERO cells (10-87 HP); and a cell line (10-87 T) derived from a 10-87 HP cell tumor xenograft in athymic nude mice. When compared with pAGMK cells, the majority of miRNAs were expressed at lower levels in 10-87 LP, 10-87 HP, and 10-87 T cells. We identified 10 up-regulated miRNAs whose level of expression correlated with VERO cell evolution from a non-tumorigenic phenotype to a tumorigenic phenotype. The overexpression of miR-376a and the polycistronic cluster of miR-376a, miR-376b and miR-376c conferred phenotypic changes to the non-tumorigenic 10-87 LP cells that mimic the tumorigenic 10-87 HP cells. Thirty percent of miRNAs that were components of the identified miRNAs in our spontaneously transformed AGMK cell model are also dysregulated in a variety of human tumors. These results may prove to be relevant to the biology of neoplastic development. In addition, one or more of these miRNAs could be biomarkers for the expression of a tumorigenic phenotype.

  10. Establishing 'quality of life' parameters using behavioural guidelines for humane euthanasia of captive non-human primates.

    PubMed

    Lambeth, Sp; Schapiro, Sj; Bernacky, Bj; Wilkerson, Gk

    2013-09-01

    Chronic pain and distress are universally accepted conditions that may adversely affect an animal's quality of life (QOL) and lead to the humane euthanasia of an animal. At most research institutions and zoological parks in the USA, a veterinarian, who has physically examined the animal and reviewed the clinical records, ultimately decides when an animal has reached a humane endpoint. To aid in the difficult process of interpreting pain and distress, we have developed specific behavioural guidelines, in addition to standard clinical information, to help define unique characteristics and traits of primates to assess and promote discussion of an individual primate's QOL, and thereby, to assist in the decision-making process regarding euthanasia. These guidelines advocate the creation of a QOL team when the animal is diagnosed with a life-threatening or debilitating chronic condition, or at the time the animal is entered into a terminal study. The team compiles a list of characteristics unique to that individual animal by utilising a questionnaire and a behavioural ethogram. This list enables the team to quantitatively assess any deviations from the established normal behavioural repertoire of that individual. Concurrently, the QOL team determines the number of behavioural deviations that are needed to trigger an immediate discussion of the necessity for humane euthanasia of the animal. The team remains intact once created, and revisits the animal's condition as frequently as deemed necessary. This process improves animal welfare by continuing the quest to optimally define QOL for captive primates, and potentially for all captive animals.

  11. Nonhuman primate models of focal cerebral ischemia

    PubMed Central

    Fan, Jingjing; Li, Yi; Fu, Xinyu; Li, Lijuan; Hao, Xiaoting; Li, Shasha

    2017-01-01

    Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model.

  12. Knowledge-guided robust MRI brain extraction for diverse large-scale neuroimaging studies on humans and non-human primates.

    PubMed

    Wang, Yaping; Nie, Jingxin; Yap, Pew-Thian; Li, Gang; Shi, Feng; Geng, Xiujuan; Guo, Lei; Shen, Dinggang

    2014-01-01

    Accurate and robust brain extraction is a critical step in most neuroimaging analysis pipelines. In particular, for the large-scale multi-site neuroimaging studies involving a significant number of subjects with diverse age and diagnostic groups, accurate and robust extraction of the brain automatically and consistently is highly desirable. In this paper, we introduce population-specific probability maps to guide the brain extraction of diverse subject groups, including both healthy and diseased adult human populations, both developing and aging human populations, as well as non-human primates. Specifically, the proposed method combines an atlas-based approach, for coarse skull-stripping, with a deformable-surface-based approach that is guided by local intensity information and population-specific prior information learned from a set of real brain images for more localized refinement. Comprehensive quantitative evaluations were performed on the diverse large-scale populations of ADNI dataset with over 800 subjects (55 ∼ 90 years of age, multi-site, various diagnosis groups), OASIS dataset with over 400 subjects (18 ∼ 96 years of age, wide age range, various diagnosis groups), and NIH pediatrics dataset with 150 subjects (5 ∼ 18 years of age, multi-site, wide age range as a complementary age group to the adult dataset). The results demonstrate that our method consistently yields the best overall results across almost the entire human life span, with only a single set of parameters. To demonstrate its capability to work on non-human primates, the proposed method is further evaluated using a rhesus macaque dataset with 20 subjects. Quantitative comparisons with popularly used state-of-the-art methods, including BET, Two-pass BET, BET-B, BSE, HWA, ROBEX and AFNI, demonstrate that the proposed method performs favorably with superior performance on all testing datasets, indicating its robustness and effectiveness.

  13. A high density of human communication-associated genes in chromosome 7q31-q36: differential expression in human and non-human primate cortices.

    PubMed

    Schneider, E; Jensen, L R; Farcas, R; Kondova, I; Bontrop, R E; Navarro, B; Fuchs, E; Kuss, A W; Haaf, T

    2012-01-01

    The human brain is distinguished by its remarkable size, high energy consumption, and cognitive abilities compared to all other mammals and non-human primates. However, little is known about what has accelerated brain evolution in the human lineage. One possible explanation is that the appearance of advanced communication skills and language has been a driving force of human brain development. The phenotypic adaptations in brain structure and function which occurred on the way to modern humans may be associated with specific molecular signatures in today's human genome and/or transcriptome. Genes that have been linked to language, reading, and/or autism spectrum disorders are prime candidates when searching for genes for human-specific communication abilities. The database and genome-wide expression analyses we present here revealed a clustering of such communication-associated genes (COAG) on human chromosomes X and 7, in particular chromosome 7q31-q36. Compared to the rest of the genome, we found a high number of COAG to be differentially expressed in the cortices of humans and non-human primates (chimpanzee, baboon, and/or marmoset). The role of X-linked genes for the development of human-specific cognitive abilities is well known. We now propose that chromosome 7q31-q36 also represents a hot spot for the evolution of human-specific communication abilities. Selective pressure on the T cell receptor beta locus on chromosome 7q34, which plays a pivotal role in the immune system, could have led to rapid dissemination of positive gene variants in hitchhiking COAG.

  14. Antipsychotic-like effect of the muscarinic acetylcholine receptor agonist BuTAC in non-human primates.

    PubMed

    Andersen, Maibritt B; Croy, Carrie Hughes; Dencker, Ditte; Werge, Thomas; Bymaster, Frank P; Felder, Christian C; Fink-Jensen, Anders

    2015-01-01

    Cholinergic, muscarinic receptor agonists exhibit functional dopamine antagonism and muscarinic receptors have been suggested as possible future targets for the treatment of schizophrenia and drug abuse. The muscarinic ligand (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (BuTAC) exhibits high affinity for muscarinic receptors with no or substantially less affinity for a large number of other receptors and binding sites, including the dopamine receptors and the dopamine transporter. In the present study, we wanted to examine the possible antipsychotic-like effects of BuTAC in primates. To this end, we investigated the effects of BuTAC on d-amphetamine-induced behaviour in antipsychotic-naive Cebus paella monkeys. Possible adverse events of BuTAC, were evaluated in the same monkeys as well as in monkeys sensitized to antipsychotic-induced extrapyramidal side effects. The present data suggests that, the muscarinic receptor ligand BuTAC exhibits antipsychotic-like behaviour in primates. The behavioural data of BuTAC as well as the new biochemical data further substantiate the rationale for the use of muscarinic M1/M2/M4-preferring receptor agonists as novel pharmacological tools in the treatment of schizophrenia.

  15. Optimal Region of the Putamen for Image-Guided Convection-Enhanced Delivery of Therapeutics in Human and Non-human Primates

    PubMed Central

    Yin, Dali; Valles, Francisco E.; Fiandaca, Massimo S.; Bringas, John; Gimenez, Francisco; Berger, Mitchel S.; Forsayeth, John; Bankiewicz, Krystof S.

    2009-01-01

    Optimal results in the direct brain delivery of brain therapeutics such as growth factors or viral vector into primate brain depends on reproducible distribution throughout the target region. In the present study, we retrospectively analyzed MRI of 25 convection-enhanced delivery (CED) infusions with MRI contrast into the putamen of non-human primates (NHP). Infused volume (Vi) was compared to total volume of distribution (Vd), vs. Vd within the target putamen. Excellent distribution of contrast agent within the putamen was obtained in 8 cases that were used to define an optimal target volume, or “green” zone. Partial or poor distribution with leakage into adjacent anatomical structures was noted in 17 cases, defining “blue” and “red” zones respectively. Quantitative containment (99 ± 1%) of infused Gadoteridol within the putamen was obtained when the cannula was placed in the green zone, 87 ± 3% in the blue zone and 49 ± 0.05% in the red zone. These results were used to determine a set of 3D stereotactic coordinates that define an optimal site for putaminal infusions in NHP and human putamen. We conclude that cannula placement and definition of optimal (green zone) stereotactic coordinates have important implications in ensuring effective delivery of therapeutics into the putamen utilizing routine stereotactic MRI localization procedures, and should be considered when local therapies such as gene transfer or protein administration are being translated into clinical therapy. PMID:19761848

  16. Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

    PubMed Central

    Ma, Kuo-Hsing; Liu, Tsung-Ta; Weng, Shao-Ju; Chen, Chien-Fu F.; Huang, Yuahn-Sieh; Chueh, Sheau-Huei; Liao, Mei-Hsiu; Chang, Kang-Wei; Sung, Chi-Chang; Hsu, Te-Hung; Huang, Wen-Sheng; Cheng, Cheng-Yi

    2016-01-01

    3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate. PMID:27941910

  17. The adjuvanticity of an O. volvulus-derived rOv-ASP-1 protein in mice using sequential vaccinations and in non-human primates.

    PubMed

    Wang, Jing; Tricoche, Nancy; Du, Lanying; Hunter, Meredith; Zhan, Bin; Goud, Gaddam; Didier, Elizabeth S; Liu, Jing; Lu, Lu; Marx, Preston A; Jiang, Shibo; Lustigman, Sara

    2012-01-01

    Adjuvants potentiate antigen-specific protective immune responses and can be key elements promoting vaccine effectiveness. We previously reported that the Onchocerca volvulus recombinant protein rOv-ASP-1 can induce activation and maturation of naïve human DCs and therefore could be used as an innate adjuvant to promote balanced Th1 and Th2 responses to bystander vaccine antigens in mice. With a few vaccine antigens, it also promoted a Th1-biased response based on pronounced induction of Th1-associated IgG2a and IgG2b antibody responses and the upregulated production of Th1 cytokines, including IL-2, IFN-γ, TNF-α and IL-6. However, because it is a protein, the rOv-ASP-1 adjuvant may also induce anti-self-antibodies. Therefore, it was important to verify that the host responses to self will not affect the adjuvanticity of rOv-ASP-1 when it is used in subsequent vaccinations with the same or different vaccine antigens. In this study, we have established rOv-ASP-1's adjuvanticity in mice during the course of two sequential vaccinations using two vaccine model systems: the receptor-binding domain (RBD) of SARS-CoV spike protein and a commercial influenza virus hemagglutinin (HA) vaccine comprised of three virus strains. Moreover, the adjuvanticity of rOv-ASP-1 was retained with an efficacy similar to that obtained when it was used for a first vaccination, even though a high level of anti-rOv-ASP-1 antibodies was present in the sera of mice before the administration of the second vaccine. To further demonstrate its utility as an adjuvant for human use, we also immunized non-human primates (NHPs) with RBD plus rOv-ASP-1 and showed that rOv-ASP-1 could induce high titres of functional and protective anti-RBD antibody responses in NHPs. Notably, the rOv-ASP-1 adjuvant did not induce high titer antibodies against self in NHPs. Thus, the present study provided a sound scientific foundation for future strategies in the development of this novel protein adjuvant.

  18. No effect of inter-group conflict on within-group harmony in non-human primates

    PubMed Central

    Grueter, Cyril C

    2013-01-01

    It has been a longstanding assumption that the threat of extra-group conflict can promote the expression of socio-positive behavior and cohesion within animal groups. I conducted a comparative analysis on the effect of inter-group conflict (indexed by home range overlap) on within-group affiliation levels (indexed by time engaged in allogrooming) in a sample of 48 primate species. There was no association between the 2 variables in a phylogenetic generalized least squares regression. I conclude that inter-group conflict may at best elicit short-term immediate changes in affiliation levels, but permanently elevated cohesion appears unique to humans with their large-scale social integration and scaled up inter-group conflict. PMID:24563713

  19. Establishing ‘quality of life’ parameters using behavioural guidelines for humane euthanasia of captive non-human primates

    PubMed Central

    Lambeth, SP; Schapiro, SJ; Bernacky, BJ; Wilkerson, GK

    2014-01-01

    Chronic pain and distress are universally accepted conditions that may adversely affect an animal’s quality of life (QOL) and lead to the humane euthanasia of an animal. At most research institutions and zoological parks in the USA, a veterinarian, who has physically examined the animal and reviewed the clinical records, ultimately decides when an animal has reached a humane endpoint. To aid in the difficult process of interpreting pain and distress, we have developed specific behavioural guidelines, in addition to standard clinical information, to help define unique characteristics and traits of primates to assess and promote discussion of an individual primate’s QOL, and thereby, to assist in the decision-making process regarding euthanasia. These guidelines advocate the creation of a QOL team when the animal is diagnosed with a life-threatening or debilitating chronic condition, or at the time the animal is entered into a terminal study. The team compiles a list of characteristics unique to that individual animal by utilising a questionnaire and a behavioural ethogram. This list enables the team to quantitatively assess any deviations from the established normal behavioural repertoire of that individual. Concurrently, the QOL team determines the number of behavioural deviations that are needed to trigger an immediate discussion of the necessity for humane euthanasia of the animal. The team remains intact once created, and revisits the animal’s condition as frequently as deemed necessary. This process improves animal welfare by continuing the quest to optimally define QOL for captive primates, and potentially for all captive animals. PMID:25505822

  20. Nonhuman primate models in translational regenerative medicine.

    PubMed

    Daadi, Marcel M; Barberi, Tiziano; Shi, Qiang; Lanford, Robert E

    2014-12-01

    Humans and nonhuman primates (NHPs) are similar in size, behavior, physiology, biochemistry, structure and function of organs, and complexity of the immune system. Research on NHPs generates complementary data that bridge translational research from small animal models to humans. NHP models of human disease offer unique opportunities to develop stem cell-based therapeutic interventions that directly address relevant and challenging translational aspects of cell transplantation therapy. These include the use of autologous induced pluripotent stem cell-derived cellular products, issues related to the immune response in autologous and allogeneic setting, pros and cons of delivery techniques in a clinical setting, as well as the safety and efficacy of candidate cell lines. The NHP model allows the assessment of complex physiological, biochemical, behavioral, and imaging end points, with direct relevance to human conditions. At the same time, the value of using primates in scientific research must be carefully evaluated and timed due to expense and the necessity for specialized equipment and highly trained personnel. Often it is more efficient and useful to perform initial proof-of-concept studies for new therapeutics in rodents and/or other species before the pivotal studies in NHPs that may eventually lead to first-in-human trials. In this report, we present how the Southwest National Primate Research Center, one of seven NIH-funded National Primate Research Centers, may help the global community in translating promising technologies to the clinical arena.

  1. A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots

    NASA Astrophysics Data System (ADS)

    Ye, Ling; Yong, Ken-Tye; Liu, Liwei; Roy, Indrajit; Hu, Rui; Zhu, Jing; Cai, Hongxing; Law, Wing-Cheung; Liu, Jianwei; Wang, Kai; Liu, Jing; Liu, Yaqian; Hu, Yazhuo; Zhang, Xihe; Swihart, Mark T.; Prasad, Paras N.

    2012-07-01

    Quantum dots have been used in biomedical research for imaging, diagnostics and sensing purposes. However, concerns over the cytotoxicity of their heavy metal constituents and conflicting results from in vitro and small animal toxicity studies have limited their translation towards clinical applications. Here, we show in a pilot study that rhesus macaques injected with phospholipid micelle-encapsulated CdSe/CdS/ZnS quantum dots do not exhibit evidence of toxicity. Blood and biochemical markers remained within normal ranges following treatment, and histology of major organs after 90 days showed no abnormalities. Our results show that acute toxicity of these quantum dots in vivo can be minimal. However, chemical analysis revealed that most of the initial dose of cadmium remained in the liver, spleen and kidneys after 90 days. This means that the breakdown and clearance of quantum dots is quite slow, suggesting that longer-term studies will be required to determine the ultimate fate of these heavy metals and the impact of their persistence in primates.

  2. Genomic and evolutionary characterization of TT virus (TTV) in tupaias and comparison with species-specific TTVs in humans and non-human primates.

    PubMed

    Okamoto, H; Nishizawa, T; Takahashi, M; Tawara, A; Peng, Y; Kishimoto, J; Wang, Y

    2001-09-01

    TT virus (TTV) was recovered from the sera of tupaias (Tupaia belangeri chinensis) by PCR using primers derived from the noncoding region of the human TTV genome, and its entire genomic sequence was determined. One tupaia TTV isolate (Tbc-TTV14) consisted of only 2199 nucleotides (nt) and had three open reading frames (ORFs), spanning 1506 nt (ORF1), 177 nt (ORF2) and 642 nt (ORF3), which were in the same orientation as the ORFs of the human prototype TTV (TA278). ORF3 was presumed to arise from a splicing of TTV mRNA, similar to reported human TTVs whose spliced mRNAs have been identified, and encoded a joint protein of 214 amino acids with a Ser-, Lys- and Arg-rich sequence at the C terminus. Tbc-TTV14 was less than 50% similar to previously reported TTVs of 3.4-3.9 kb and TTV-like mini viruses (TLMVs) of 2.8-3.0 kb isolated from humans and non-human primates, and known animal circoviruses. Although Tbc-TTV14 has a genomic length similar to animal circoviruses (1.8-2.3 kb), Tbc-TTV14 resembled TTVs and TLMVs with regard to putative genomic organization and transcription profile. Conserved motifs were commonly observed in the coding and noncoding regions of the Tbc-TTV14 genome and in all TTV and TLMV genomes. Phylogenetic analysis revealed that Tbc-TTV14 is the closest to TLMVs, and is closer to TTVs isolated from tamarin and douroucouli than to TTVs isolated from humans and chimpanzees. These results indicate that tupaias are naturally infected with a new TTV species that has not been identified among primates.

  3. Erythrocytes from GGTA1/CMAH knockout pigs: implications for xenotransfusion and testing in non-human primates

    PubMed Central

    Wang, Zheng-Yu; Burlak, Christopher; Estrada, Jose L.; Li, Ping; Tector, Matthew F.; Tector, A. Joseph

    2015-01-01

    compared to GGTA1 KO erythrocytes, but markedly increased 3-fold by baboon serum IgG. Human IgM binding was decreased 227-fold on GGTA1/CMAH KO erythrocytes compared to GGTA1 KO erythrocytes, but enhanced 5-fold by baboon serum IgM. Conclusions Removal of aGal and Neu5Gc antigens from pig erythrocytes significantly reduced human preformed antibody-mediated cytotoxicity but may have complicated future in vivo analysis by enhancing reactivity from baboons. The creation of the GGTA1/CMAH KO pig has provided the xenotransplantion researcher with organs and cells that attract fewer human antibodies than baboon and our closest primate relative, chimpanzee. These finding suggest that while GGTA1/CMAH KO erythrocytes may be useful for human transfusions, in vivo testing in the baboon may not provide a direct transplation to the clinic. PMID:24986655

  4. A retrospective evaluation of species-specific sensitivity for neurological signs in toxicological studies: Is the dog more sensitive than the non-human primate?

    PubMed

    Backes, Kathrin; Lorenz, Helga; Laplanche, Loic; Hudzik, Thomas J; Potschka, Heidrun; Hempel, Katja

    2016-01-22

    Selection of the appropriate non-rodent species in preclinical programs is crucial for good translatability and human safety. There is no data available in the literature which provides exact comparison of dog and non-human primate (NHP) sensitivity regarding neurological signs in toxicological studies. We performed a retrospective analysis of 174 toxicity studies with 15 neuroscience substances. Neurological signs in dogs and NHPs were evaluated in correlation to exposure data. Overall incidence of substance induced convulsions was similar in both species and no gender differences were observed. The reported liability of beagles to spontaneous convulsions was not confirmed in our studies. The symptom tremor showed the best inter-species translatability. The current toxicological study design does not include exposure assessment at the time-point of neurological signs, therefore, we propose to include additional toxicokinetic samples. Our analysis revealed factors including housing, handling, and behavior, which prevents direct species comparison. In addition only one non-rodent species is routinely tested in development programs, therefore data for both species is rare. We however, had sufficient data which enabled comparison for one compound. In the spirit of 3Rs further examples should be evaluated.

  5. Surveillance for Yellow Fever Virus in Non-Human Primates in Southern Brazil, 2001–2011: A Tool for Prioritizing Human Populations for Vaccination

    PubMed Central

    Almeida, Marco A. B.; Cardoso, Jader da C.; dos Santos, Edmilson; da Fonseca, Daltro F.; Cruz, Laura L.; Faraco, Fernando J. C.; Bercini, Marilina A.; Vettorello, Kátia C.; Porto, Mariana A.; Mohrdieck, Renate; Ranieri, Tani M. S.; Schermann, Maria T.; Sperb, Alethéa F.; Paz, Francisco Z.; Nunes, Zenaida M. A.; Romano, Alessandro P. M.; Costa, Zouraide G.; Gomes, Silvana L.; Flannery, Brendan

    2014-01-01

    In Brazil, epizootics among New World monkey species may indicate circulation of yellow fever (YF) virus and provide early warning of risk to humans. Between 1999 and 2001, the southern Brazilian state of Rio Grande do Sul initiated surveillance for epizootics of YF in non-human primates to inform vaccination of human populations. Following a YF outbreak, we analyzed epizootic surveillance data and assessed YF vaccine coverage, timeliness of implementation of vaccination in unvaccinated human populations. From October 2008 through June 2009, circulation of YF virus was confirmed in 67 municipalities in Rio Grande do Sul State; vaccination was recommended in 23 (34%) prior to the outbreak and in 16 (24%) within two weeks of first epizootic report. In 28 (42%) municipalities, vaccination began more than two weeks after first epizootic report. Eleven (52%) of 21 laboratory-confirmed human YF cases occurred in two municipalities with delayed vaccination. By 2010, municipalities with confirmed YF epizootics reported higher vaccine coverage than other municipalities that began vaccination. In unvaccinated human populations timely response to epizootic events is critical to prevent human yellow fever cases. PMID:24625681

  6. Ebola virus genome plasticity as a marker of its passaging history: a comparison of in vitro passaging to non-human primate infection.

    PubMed

    Kugelman, Jeffrey R; Lee, Michael S; Rossi, Cynthia A; McCarthy, Sarah E; Radoshitzky, Sheli R; Dye, John M; Hensley, Lisa E; Honko, Anna; Kuhn, Jens H; Jahrling, Peter B; Warren, Travis K; Whitehouse, Chris A; Bavari, Sina; Palacios, Gustavo

    2012-01-01

    To identify polymorphic sites that could be used as biomarkers of Ebola virus passage history, we repeatedly amplified Ebola virus (Kikwit variant) in vitro and in vivo and performed deep sequencing analysis of the complete genomes of the viral subpopulations. We then determined the sites undergoing selection during passage in Vero E6 cells. Four locations within the Ebola virus Kikwit genome were identified that together segregate cell culture-passaged virus and virus obtained from infected non-human primates. Three of the identified sites are located within the glycoprotein gene (GP) sequence: the poly-U (RNA editing) site at position 6925, as well as positions 6677, and 6179. One site was found in the VP24 gene at position 10833. In all cases, in vitro and in vivo, both populations (majority and minority variants) were maintained in the viral swarm, with rapid selections occurring after a few passages or infections. This analysis approach will be useful to differentiate whether filovirus stocks with unknown history have been passaged in cell culture and may support filovirus stock standardization for medical countermeasure development.

  7. Structural architecture of the social network of a non-human primate (Macaca sylvanus): a study of its topology in La Forêt des Singes, Rocamadour.

    PubMed

    Sosa, Sebastian

    2014-01-01

    For a decade, technological or natural networks have appeared to have a common mathematical architecture. This type of architecture has a node connectivity which follows a power law distribution. This architecture confers to these networks a resistance property to the loss of nodes. Such properties are advantageous for evolutional networks through time. Thus, this architecture can be expected in animal social networks. Another characteristic commonly met concerns the structuration of the network into communities by the mechanism of assortative mixing by vertex degree (i.e. by the number of ties individuals have). Such a structure is a reflection of evolutional mechanisms: the preferential attachment and the triadic closure processes. Using recent analytical techniques on an affiliative social network in a non-human primate species (Macaca sylvanus), we analysed the mathematical architecture and its properties. We demonstrate that in spite of the use of a recent protocol supposed to permit this type of analysis, the type of distribution cannot be clearly determined, encouraging us to carefully interpret the results obtained until then. Nevertheless, we observed interesting properties of the network at an ecological and evolutional level with network resilience that allows a cohesive society to be maintained even when faced with a catastrophe (high predation, epidemic).

  8. Changes in Cerebral Blood Flow during an Alteration in Glycemic State in a Large Non-human Primate (Papio hamadryas sp.)

    PubMed Central

    Kochunov, Peter; Wey, Hsiao-Ying; Fox, Peter T.; Lancaster, Jack L.; Davis, Michael D.; Wang, Danny J. J.; Lin, Ai-Ling; Bastarrachea, Raul A.; Andrade, Marcia C. R.; Mattern, Vicki; Frost, Patrice; Higgins, Paul B.; Comuzzie, Anthony G.; Voruganti, Venkata S.

    2017-01-01

    Changes in cerebral blood flow (CBF) during a hyperglycemic challenge were mapped, using perfusion-weighted MRI, in a group of non-human primates. Seven female baboons were fasted for 16 h prior to 1-h imaging experiment, performed under general anesthesia, that consisted of a 20-min baseline, followed by a bolus infusion of glucose (500 mg/kg). CBF maps were collected every 7 s and blood glucose and insulin levels were sampled at regular intervals. Blood glucose levels rose from 51.3 ± 10.9 to 203.9 ± 38.9 mg/dL and declined to 133.4 ± 22.0 mg/dL, at the end of the experiment. Regional CBF changes consisted of four clusters: cerebral cortex, thalamus, hypothalamus, and mesencephalon. Increases in the hypothalamic blood flow occurred concurrently with the regulatory response to systemic glucose change, whereas CBF declined for other clusters. The return to baseline of hypothalamic blood flow was observed while CBF was still increasing in other brain regions. The spatial pattern of extra-hypothalamic CBF changes was correlated with the patterns of several cerebral networks including the default mode network. These findings suggest that hypothalamic blood flow response to systemic glucose levels can potentially be explained by regulatory activity. The response of extra-hypothalamic clusters followed a different time course and its spatial pattern resembled that of the default-mode network. PMID:28261040

  9. Changes in Cerebral Blood Flow during an Alteration in Glycemic State in a Large Non-human Primate (Papio hamadryas sp.).

    PubMed

    Kochunov, Peter; Wey, Hsiao-Ying; Fox, Peter T; Lancaster, Jack L; Davis, Michael D; Wang, Danny J J; Lin, Ai-Ling; Bastarrachea, Raul A; Andrade, Marcia C R; Mattern, Vicki; Frost, Patrice; Higgins, Paul B; Comuzzie, Anthony G; Voruganti, Venkata S

    2017-01-01

    Changes in cerebral blood flow (CBF) during a hyperglycemic challenge were mapped, using perfusion-weighted MRI, in a group of non-human primates. Seven female baboons were fasted for 16 h prior to 1-h imaging experiment, performed under general anesthesia, that consisted of a 20-min baseline, followed by a bolus infusion of glucose (500 mg/kg). CBF maps were collected every 7 s and blood glucose and insulin levels were sampled at regular intervals. Blood glucose levels rose from 51.3 ± 10.9 to 203.9 ± 38.9 mg/dL and declined to 133.4 ± 22.0 mg/dL, at the end of the experiment. Regional CBF changes consisted of four clusters: cerebral cortex, thalamus, hypothalamus, and mesencephalon. Increases in the hypothalamic blood flow occurred concurrently with the regulatory response to systemic glucose change, whereas CBF declined for other clusters. The return to baseline of hypothalamic blood flow was observed while CBF was still increasing in other brain regions. The spatial pattern of extra-hypothalamic CBF changes was correlated with the patterns of several cerebral networks including the default mode network. These findings suggest that hypothalamic blood flow response to systemic glucose levels can potentially be explained by regulatory activity. The response of extra-hypothalamic clusters followed a different time course and its spatial pattern resembled that of the default-mode network.

  10. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. Purpose: The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, medial gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  11. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, media] gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  12. Surveillance for yellow Fever virus in non-human primates in southern Brazil, 2001-2011: a tool for prioritizing human populations for vaccination.

    PubMed

    Almeida, Marco A B; Cardoso, Jader da C; Dos Santos, Edmilson; da Fonseca, Daltro F; Cruz, Laura L; Faraco, Fernando J C; Bercini, Marilina A; Vettorello, Kátia C; Porto, Mariana A; Mohrdieck, Renate; Ranieri, Tani M S; Schermann, Maria T; Sperb, Alethéa F; Paz, Francisco Z; Nunes, Zenaida M A; Romano, Alessandro P M; Costa, Zouraide G; Gomes, Silvana L; Flannery, Brendan

    2014-03-01

    In Brazil, epizootics among New World monkey species may indicate circulation of yellow fever (YF) virus and provide early warning of risk to humans. Between 1999 and 2001, the southern Brazilian state of Rio Grande do Sul initiated surveillance for epizootics of YF in non-human primates to inform vaccination of human populations. Following a YF outbreak, we analyzed epizootic surveillance data and assessed YF vaccine coverage, timeliness of implementation of vaccination in unvaccinated human populations. From October 2008 through June 2009, circulation of YF virus was confirmed in 67 municipalities in Rio Grande do Sul State; vaccination was recommended in 23 (34%) prior to the outbreak and in 16 (24%) within two weeks of first epizootic report. In 28 (42%) municipalities, vaccination began more than two weeks after first epizootic report. Eleven (52%) of 21 laboratory-confirmed human YF cases occurred in two municipalities with delayed vaccination. By 2010, municipalities with confirmed YF epizootics reported higher vaccine coverage than other municipalities that began vaccination. In unvaccinated human populations timely response to epizootic events is critical to prevent human yellow fever cases.

  13. Targeting accuracy and closing timeline of the microbubble-enhanced focused ultrasound blood-brain barrier opening in non-human primates

    NASA Astrophysics Data System (ADS)

    Marquet, Fabrice; Tung, Yao-Sheng; Teichert, Tobias; Wu, Shih-Ying; Wang, Shutao; Downs, Matthew; Ferrera, Vincent P.; Konofagou, Elisa E.

    2012-11-01

    The delivery of drugs to specific neural targets faces two fundamental problems: Most drugs do not cross the blood-brain barrier and those that do spread to all parts of the brain. To date there exists only one non-invasive methodology with the potential to solve these problems: selective blood-brain barrier disruption using micro-bubble enhanced focused ultrasound. We have recently developed a single-element 500 kHz spherical transducer ultrasound setup for use in the non-human primate. Using this system for selective blood-brain barrier disruption is technically no more challenging than positioning a TMS coil, and does not rely on MRI-guided targeting or expensive phased array ultrasound systems. So far, however, the targeting accuracy that can be achieved with this system has not been quantified systematically. Here we tested the accuracy of the system by targeting the caudate nucleus of the basal ganglia in two macaque monkeys. Our results show that average in-plane error of the system is on the order of 2 mm and targeting error in depth, i.e., along the ultrasound path, is even smaller and averaged 1.2 mm. In summary, targeting accuracy of our system is good enough to enable the selective delivery of drugs to specific sub-structures of the basal ganglia.

  14. Cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet.

    PubMed

    Kimani, S; Moterroso, V; Morales, P; Wagner, J; Kipruto, S; Bukachi, F; Maitai, C; Tshala-Katumbay, D

    2014-04-01

    We sought to elucidate the impact of diet, cyanide or cyanate exposure on mammalian cyanide detoxification capabilities (CDC). Male rats (~8 weeks old) (N=52) on 75% sulfur amino acid (SAA)-deficient diet were treated with NaCN (2.5mg/kg bw) or NaOCN (50mg/kg bw) for 6 weeks. Macaca fascicularis monkeys (~12 years old) (N=12) were exclusively fed cassava for 5 weeks. CDC was assessed in plasma, or spinal cord, or brain. In rats, NaCN induced seizures under SAA-restricted diet whereas NaOCN induced motor deficits. No deficits were observed in non-human primates. Under normal diet, the CDC were up to ~80× faster in the nervous system (14 ms to produce one μmol of thiocyanate from the detoxification of cyanide) relative to plasma. Spinal cord CDC was impaired by NaCN, NaOCN, or SAA deficiency. In M. fascicularis, plasma CDC changed proportionally to total proteins (r=0.43; p<0.001). The plasma CDC was ~2× relative to that of rodents. The nervous system susceptibility to cyanide may result from a "multiple hit" by the toxicity of cyanide or its cyanate metabolite, the influences of dietary deficiencies, and the tissue variations in CDC. Chronic dietary reliance on cassava may cause metabolic derangement including poor CDC.

  15. Effect of body mass distribution on the ontogeny of positional behaviors in non-human primates: Longitudinal follow-up of infant captive olive baboons (Papio anubis).

    PubMed

    Druelle, François; Aerts, Peter; Berillon, Gilles

    2016-11-01

    The diversity of primates' positional capabilities is unique among mammals. Indeed, they exhibit a daily repertoire composed of various locomotor and postural modes that may be linked to their particular morphological pattern. Because ontogeny undergoes parallel behavioral and morphological modifications, it may be useful to investigate the biomechanical consequences of the changing body shape. We, therefore, collected accurate quantitative and longitudinal data on positional behaviors, body mass distribution patterns, activities, and environment on a sample of six infant olive baboons, Papio anubis. These baboons are kept at the Primatology Station of the CNRS, France, where they live within the same social group. Individual behaviors were quantified using the focal sampling method. The body mass distribution was estimated according to a geometric model based on direct external measurements. Multivariate analysis enabled us to analyze the interactions between the data. Our results show that body mass distribution changes together with the ontogenetic changes in positional behaviors. At an early age, individuals have distally heavy segment masses in the limbs and an important fraction of the behavioral repertoire involves efficient grasping abilities. At the end of infancy, the same individuals have relatively more mass in proximal segments of the limbs and the proportion of quadrupedal walking is significantly higher while other climbing and suspensory behaviors decreased substantially. The present study experimentally confirms the association between body mass distribution and the positional repertoire of primates. These relationships, when interpreted in the context of basic biomechanical concepts, may improve our understanding of primate locomotion. We discuss further the implications of these functional relationships when modeling the evolutionary pathway of primates. Am. J. Primatol. 78:1201-1221, 2016. © 2016 Wiley Periodicals, Inc.

  16. Emotion Evaluation and Response Slowing in a Non-Human Primate: New Directions for Cognitive Bias Measures of Animal Emotion?

    PubMed Central

    Bethell, Emily J.; Holmes, Amanda; MacLarnon, Ann; Semple, Stuart

    2016-01-01

    The cognitive bias model of animal welfare assessment is informed by studies with humans demonstrating that the interaction between emotion and cognition can be detected using laboratory tasks. A limitation of cognitive bias tasks is the amount of training required by animals prior to testing. A potential solution is to use biologically relevant stimuli that trigger innate emotional responses. Here; we develop a new method to assess emotion in rhesus macaques; informed by paradigms used with humans: emotional Stroop; visual cueing and; in particular; response slowing. In humans; performance on a simple cognitive task can become impaired when emotional distractor content is displayed. Importantly; responses become slower in anxious individuals in the presence of mild threat; a pattern not seen in non-anxious individuals; who are able to effectively process and disengage from the distractor. Here; we present a proof-of-concept study; demonstrating that rhesus macaques show slowing of responses in a simple touch-screen task when emotional content is introduced; but only when they had recently experienced a presumably stressful veterinary inspection. Our results indicate the presence of a subtle “cognitive freeze” response; the measurement of which may provide a means of identifying negative shifts in emotion in animals. PMID:26761035

  17. Foodborne Transmission of Bovine Spongiform Encephalopathy to Non-Human Primates Results in Preclinical Rapid-Onset Obesity

    PubMed Central

    Strom, Alexander; Yutzy, Barbara; Kruip, Carina; Ooms, Mark; Schloot, Nanette C.; Roden, Michael; Scott, Fraser W.; Loewer, Johannes; Holznagel, Edgar

    2014-01-01

    Obesity has become one of the largest public health challenges worldwide. Recently, certain bacterial and viral pathogens have been implicated in the pathogenesis of obesity. In the present study, we retrospectively analyzed clinical data, plasma samples and post-mortem tissue specimens derived from a risk assessment study in bovine spongiform encephalopathy (BSE)-infected female cynomolgus monkeys (Macaca fascicularis). The original study design aimed to determine minimal infectious doses after oral or intracerebral (i.c.) infection of macaques to assess the risk for humans. High-dose exposures resulted in 100% attack rates and a median incubation time of 4.7 years as described previously. Retrospective analyses of clinical data from high-dosed macaques revealed that foodborne BSE transmission caused rapid weight gain within 1.5 years post infection (β = 0.915; P<0.0001) which was not seen in age- and sex-matched control animals or i.c. infected animals. The rapid-onset obesity was not associated with impaired pancreatic islet function or glucose metabolism. In the early preclinical phase of oral transmission associated with body weight gain, prion accumulation was confined to the gastrointestinal tract. Intriguingly, immunohistochemical findings suggest that foodborne BSE transmission has a pathophysiological impact on gut endocrine cells which may explain rapid weight gain. To our knowledge, this is the first experimental model which clearly demonstrates that foodborne pathogens can induce obesity. PMID:25090610

  18. Foodborne transmission of bovine spongiform encephalopathy to non-human primates results in preclinical rapid-onset obesity.

    PubMed

    Strom, Alexander; Yutzy, Barbara; Kruip, Carina; Ooms, Mark; Schloot, Nanette C; Roden, Michael; Scott, Fraser W; Loewer, Johannes; Holznagel, Edgar

    2014-01-01

    Obesity has become one of the largest public health challenges worldwide. Recently, certain bacterial and viral pathogens have been implicated in the pathogenesis of obesity. In the present study, we retrospectively analyzed clinical data, plasma samples and post-mortem tissue specimens derived from a risk assessment study in bovine spongiform encephalopathy (BSE)-infected female cynomolgus monkeys (Macaca fascicularis). The original study design aimed to determine minimal infectious doses after oral or intracerebral (i.c.) infection of macaques to assess the risk for humans. High-dose exposures resulted in 100% attack rates and a median incubation time of 4.7 years as described previously. Retrospective analyses of clinical data from high-dosed macaques revealed that foodborne BSE transmission caused rapid weight gain within 1.5 years post infection (β = 0.915; P<0.0001) which was not seen in age- and sex-matched control animals or i.c. infected animals. The rapid-onset obesity was not associated with impaired pancreatic islet function or glucose metabolism. In the early preclinical phase of oral transmission associated with body weight gain, prion accumulation was confined to the gastrointestinal tract. Intriguingly, immunohistochemical findings suggest that foodborne BSE transmission has a pathophysiological impact on gut endocrine cells which may explain rapid weight gain. To our knowledge, this is the first experimental model which clearly demonstrates that foodborne pathogens can induce obesity.

  19. Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor.

    PubMed Central

    Genain, C P; Roberts, T; Davis, R L; Nguyen, M H; Uccelli, A; Faulds, D; Li, Y; Hedgpeth, J; Hauser, S L

    1995-01-01

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 PMID:7536938

  20. Early life stress as a risk factor for mental health: Role of neurotrophins from rodents to non-human primates

    PubMed Central

    Cirulli, Francesca; Francia, Nadia; Berry, Alessandra; Aloe, Luigi; Alleva, Enrico; Suomi, Stephen J.

    2009-01-01

    Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood. The epigenetic factors involved in transducing specific features of the rearing environment into stable changes in brain and behavioral plasticity have only begun to be elucidated. Neurotrophic factors, such as Nerve Growth Factor (NGF) and Brain-derived neurotrophic factor (BDNF), are affected by stress and play a major role in brain development and in the trophism of specific neuronal networks involved in cognitive function and in mood disorders. In addition to the central nervous system, these effectors are produced by peripheral tissues, thus being in a position to integrate the response to external challenges. In this paper we will review data, obtained from animal models, indicating that early maternal deprivation stress can affect neurotrophin levels, suggesting that they might be involved in the mechanisms underlying the mother-infant relationship. Maladaptive or repeated activation of NGF and BDNF, early during postnatal life, may influence stress sensitivity at adulthood and increase vulnerability for stress-related psychopathology. PMID:18817811

  1. The variability of multisensory processes of natural stimuli in human and non-human primates in a detection task

    PubMed Central

    Juan, Cécile; Cappe, Céline; Alric, Baptiste; Roby, Benoit; Gilardeau, Sophie; Barone, Pascal; Girard, Pascal

    2017-01-01

    Background Behavioral studies in both human and animals generally converge to the dogma that multisensory integration improves reaction times (RTs) in comparison to unimodal stimulation. These multisensory effects depend on diverse conditions among which the most studied were the spatial and temporal congruences. Further, most of the studies are using relatively simple stimuli while in everyday life, we are confronted to a large variety of complex stimulations constantly changing our attentional focus over time, a modality switch that can impact on stimuli detection. In the present study, we examined the potential sources of the variability in reaction times and multisensory gains with respect to the intrinsic features of a large set of natural stimuli. Methodology/Principle findings Rhesus macaque monkeys and human subjects performed a simple audio-visual stimulus detection task in which a large collection of unimodal and bimodal natural stimuli with semantic specificities was presented at different saliencies. Although we were able to reproduce the well-established redundant signal effect, we failed to reveal a systematic violation of the race model which is considered to demonstrate multisensory integration. In both monkeys and human species, our study revealed a large range of multisensory gains, with negative and positive values. While modality switch has clear effects on reaction times, one of the main causes of the variability of multisensory gains appeared to be linked to the intrinsic physical parameters of the stimuli. Conclusion/Significance Based on the variability of multisensory benefits, our results suggest that the neuronal mechanisms responsible of the redundant effect (interactions vs. integration) are highly dependent on the stimulus complexity suggesting different implications of uni- and multisensory brain regions. Further, in a simple detection task, the semantic values of individual stimuli tend to have no significant impact on task

  2. Increased expression of connective tissue growth factor (CTGF) in multiple organs after exposure of non-human primates (NHP) to lethal doses of radiation

    PubMed Central

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G.; Gibbs, Allison M.; Smith, Cassandra P.; Taylor-Howell, Cheryl; Kearney, Sean R.; MacVittie, Thomas J.

    2015-01-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP, and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition respectively, suggesting possible crosstalk between spleen and other organs. Our data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs. PMID:26425899

  3. Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine.

    PubMed

    Gupta, Gaurav; Giannino, Viviana; Rishi, Narayan; Glueck, Reinhard

    2016-09-07

    Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. HPVs are oncogenic small double-stranded DNA viruses that are the primary causal agent of cervical cancer and other types of cancers, including in the anus, oropharynx, vagina, vulva, and penis. Prophylactic vaccination against HPV is an attractive strategy for preventing cervical cancer and some other types of cancers. However, there are few safe and effective vaccines against HPV infections. Current first-generation commercial HPV vaccines are expensive to produce and deliver. The goal of this study was to develop an alternate potent HPV recombinant L1-based vaccines by producing HPV virus-like particles into a vaccine that is currently used worldwide. Live attenuated measles virus (MV) vaccines have a well-established safety and efficacy record, and recombinant MV (rMV) produced by reverse genetics may be useful for generating candidate HPV vaccines to meet the needs of the developing world. We studied in non-human primate rMV-vectored HPV vaccine in parallel with a classical alum adjuvant recombinant HPV16L1 and 18L1 protein vaccine produced in Pichia pastoris. A combined prime-boost approach using both vaccines was evaluated, as well as immune interference due to pre-existing immunity against the MV. The humoral immune response induced by the MV, Pichia-expressed vaccine, and their combination as priming and boosting approaches was found to elicit HPV16L1 and 18L1 specific total IgG and neutralizing antibody titres. Pre-existing antibodies against measles did not prevent the immune response against HPV16L1 and 18L1.

  4. A non-glycosylated, plant-produced human monoclonal antibody against anthrax protective antigen protects mice and non-human primates from B. anthracis spore challenge.

    PubMed

    Mett, Vadim; Chichester, Jessica A; Stewart, Michelle L; Musiychuk, Konstantin; Bi, Hong; Reifsnyder, Carolyn J; Hull, Anna K; Albrecht, Mark T; Goldman, Stanley; Baillie, Les W J; Yusibov, Vidadi

    2011-01-01

    The health and economic burden of infectious diseases in general and bioterrorism in particular necessitate the development of medical countermeasures. One proven approach to reduce the disease burden and spread of pathogen is treatment with monoclonal antibodies (mAb). mAbs can prevent or reduce severity of the disease by variety of mechanisms, including neutralizing pathogen growth, limiting its spread from infected to adjacent cells, or by inhibiting biological activity of toxins, such as anthrax lethal toxin. Here, we report the production of glycosylated (pp-mAb (PA) ) and non-glycosylated (pp-mAb (PANG) ) versions of a plant-derived mAb directed against protective antigen (PA) of Bacillus anthracis in Nicotiana benthamiana plants using agroinfiltration. Both forms of the antibody were able to neutralize anthrax lethal toxin activity in vitro and protect mice against an intraperitoneal challenge with spores of B. anthracis Sterne strain. A single 180 µg intraperitoneal dose of pp-mAb (PA) or pp-mAb (PANG) provided 90% and 100% survival, respectively. When tested in non-human primates, pp-mAb (PANG) was demonstrated to be superior to pp-mAb (PA) in that it had a significantly longer terminal half-life and conferred 100% protection against a lethal dose of aerosolized anthrax spore challenge after a single 5 mg/kg intravenous dose compared to a 40% survival rate conferred by pp-mAb (PA) . This study demonstrates the potential of a plant-produced non-glycosylated antibody as a useful tool for the treatment of inhalation anthrax.

  5. Characterization of Enteroviruses from non-human primates in cameroon revealed virus types widespread in humans along with candidate new types and species.

    PubMed

    Sadeuh-Mba, Serge Alain; Bessaud, Maël; Joffret, Marie-Line; Endegue Zanga, Marie-Claire; Balanant, Jean; Mpoudi Ngole, Eitel; Njouom, Richard; Reynes, Jean-Marc; Delpeyroux, Francis; Rousset, Dominique

    2014-01-01

    Enteroviruses (EVs) infecting African Non-Human Primates (NHP) are still poorly documented. This study was designed to characterize the genetic diversity of EVs among captive and wild NHP in Cameroon and to compare this diversity with that found in humans. Stool specimens were collected in April 2008 in NHP housed in sanctuaries in Yaounde and neighborhoods. Moreover, stool specimens collected from wild NHP from June 2006 to October 2008 in the southern rain forest of Cameroon were considered. RNAs purified directly from stool samples were screened for EVs using a sensitive RT-nested PCR targeting the VP1 capsid coding gene whose nucleotide sequence was used for molecular typing. Captive chimpanzees (Pan troglodytes) and gorillas (Gorilla gorilla) were primarily infected by EV types already reported in humans in Cameroon and elsewhere: Coxsackievirus A13 and A24, Echovirus 15 and 29, and EV-B82. Moreover EV-A119, a novel virus type recently described in humans in central and west Africa, was also found in a captive Chimpanzee. EV-A76, which is a widespread virus in humans, was identified in wild chimpanzees, thus suggesting its adaptation and parallel circulation in human and NHP populations in Cameroon. Interestingly, some EVs harbored by wild NHP were genetically distinct from all existing types and were thus assigned as new types. One chimpanzee-derived virus was tentatively assigned as EV-J121 in the EV-J species. In addition, two EVs from wild monkeys provisionally registered as EV-122 and EV-123 were found to belong to a candidate new species. Overall, this study indicates that the genetic diversity of EVs among NHP is more important than previously known and could be the source of future new emerging human viral diseases.

  6. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

    PubMed

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G; Gibbs, Allison M; Smith, Cassandra P; Taylor-Howell, Cheryl; Kearney, Sean R; MacVittie, Thomas J

    2015-11-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.

  7. Effects of dietary resveratrol on the sleep-wake cycle in the non-human primate gray mouse lemur (Microcebus murinus).

    PubMed

    Pifferi, F; Rahman, A; Languille, S; Auffret, A; Babiloni, C; Blin, O; Lamberty, Y; Richardson, J C; Aujard, F

    2012-04-01

    Converging evidence shows that the non-human primate gray mouse lemur (Microcebus murinus) is ideal for the study of the aging process and for testing the effects of new therapies and dietary interventions on age-associated pathologies. One such dietary supplement is resveratrol (RSV), a dietary polyphenolic compound with several positive effects on metabolic functions and longevity. However, little is known about the effect of RSV on the lemur sleep-wake cycle, which reflects mammalian brain function and health. In the present study, the authors investigated this effect by comparing sleep-wake cycles in adult lemurs based on electroencephalographic (EEG) rhythms. The effect of short-term RSV supplementation on the sleep-wake cycle of mouse lemurs was evaluated in entrained conditions (long-day photoperiods, light:dark 14:10). After 3 wks of RSV supplementation, the animals exhibited a significantly increased proportion of active-wake time, occurring mainly during the resting phase of the sleep-wake cycle (+163%). The increase in active-wake time with RSV supplementation was accompanied by a significant reduction of both paradoxical sleep (-95%) and slow-wave sleep (-38%). These changes mainly occurred during the resting phase of the sleep-wake cycle (RSV supplementation induced negligible changes in active-wake time during the active phase of the sleep-wake cycle). The present data suggest that RSV may be a potent regulator of sleep-wake rhythms and could be of major interest in the study of sleep perturbations associated with aging and neuropathology.

  8. Anti-nicotine vaccines: Comparison of adjuvanted CRM197 and Qb-VLP conjugate formulations for immunogenicity and function in non-human primates.

    PubMed

    McCluskie, Michael J; Thorn, Jennifer; Gervais, David P; Stead, David R; Zhang, Ningli; Benoit, Michelle; Cartier, Janna; Kim, In-Jeong; Bhattacharya, Keshab; Finneman, Jari I; Merson, James R; Davis, Heather L

    2015-12-01

    Anti-nicotine vaccines comprise nicotine-like haptens conjugated to a carrier protein plus adjuvant(s). Unfortunately, those tested clinically have failed to improve overall long term quit rates. We had shown in mice that carrier, hapten, linker, hapten load (number of haptens per carrier molecule), aggregation and adducts, as well as adjuvants influence the function of antibodies (Ab) induced. Herein, we tested an optimized antigen, NIC7-CRM, comprised of 5-aminoethoxy-nicotine (NIC7) conjugated to genetically detoxified diphtheria toxin (CRM197), with hapten load of ~16, no aggregation (~100% monomer) and minimal adducts. NIC7-CRM was tested in non-human primates (NHP) and compared to NIC-VLP, which has the same hapten and carrier as the clinical-stage CYT002-NicQb but a slightly different linker and lower hapten load. With alum as sole adjuvant, NIC7-CRM was superior to NIC-VLP for Ab titer, avidity and ex vivo function (83% and 27% nicotine binding at 40ng/mL respectively), but equivalent for in vivo function after intravenous [IV] nicotine challenge (brain levels reduced ~10%). CpG adjuvant added to NIC7-CRM/alum further enhanced the Ab responses and both ex vivo function (100% bound) and in vivo function (~80% reduction in brain). Thus, both optimal antigen design and CpG adjuvant were required to achieve a highly functional vaccine. The compelling NHP data with NIC7-CRM with alum/CpG supported human testing, currently underway.

  9. Advances in Thin Tissue Golgi-Cox Impregnation: Fast, Reliable Methods for Multi-Assay Analyses in Rodent and Non-human Primate Brain

    PubMed Central

    Levine, Nathan D.; Rademacher, David J.; Collier, Timothy J.; O’Malley, Jennifer A.; Kells, Adrian P.; Sebastian, Waldy San; Bankiewicz, Krystof S.; Steece-Collier, Kathy

    2013-01-01

    In 1873 Camillo Golgi discovered a staining technique that allowed for the visualization of whole neurons within the brain, initially termed ‘the black reaction’ and is now known as Golgi impregnation. Despite the capricious nature of this method, Golgi impregnation remains a widely used method for whole neuron visualization and analysis of dendritic arborization and spine quantification. We describe a series of reliable, modified ‘Golgi-Cox’ impregnation methods that complement some existing methods and have several advantages over traditional whole brain ‘Golgi’ impregnation. First, these methods utilize 60–100μm thick brain sections, which allows for fast, reliable impregnation of neurons in rats (7–14 days) and non-human primates (NHP) (30 days) while avoiding the pitfalls of other ‘rapid Golgi’ techniques traditionally employed with thin sections. Second, these methods employ several common tissue fixatives, resulting in high quality neuron impregnation in brain sections from acrolein, glutaraldehyde, and paraformaldehyde perfused rats, and in glutaraldehyde perfused NHP brain tissue. Third, because thin sections are obtained on a vibratome prior to processing, alternate sections of brain tissue can be used for additional analyses such as immunohistochemistry or electron microscopy. This later advantage allows for comparison of, for example, dendrite morphology in sections adjacent to pertinent histochemical markers or ultrastructural components. Finally, we describe a method for simultaneous light microscopic visualization of both tyrosine hydroxylase immunohistochemistry and Golgi impregnation in the same tissue section. Thus, the methods described here allow for fast, high quality Golgi impregnation and conserve experimental subjects by allowing multiple analyses within an individual animal. PMID:23313849

  10. The FcγR of humans and non-human primates and their interaction with IgG: implications for induction of inflammation, resistance to infection and the use of therapeutic monoclonal antibodies.

    PubMed

    Hogarth, P Mark; Anania, Jessica C; Wines, Bruce D

    2014-01-01

    Considerable effort has focused on the roles of the individual members of the FcγR receptor (FcγR) family in inflammatory diseases and humoral immunity. Recent work has revealed major roles in infection and in particular HIV pathogenesis and immunity. In addition, FcγR functions underpin the action of many of the successful therapeutic monoclonal antibodies. This emphasises the need for a greater understanding of FcγR function in humans and in the NHP which provides a key model for human immunity and preclinical testing of antibodies. We discuss recent key aspects of the human FcγR receptor biology and structure to define differences and similarities in activity between the human and macaque Fc receptors. These differences and similarities nuance the interpretation of infection and vaccine studies in the macaque. Indeed passive IgG antibody protection in lentivirus infection models in the macaque provided early evidence for the role of Fc receptors in anti-HIV immunity that have subsequently gained support from human vaccine trials. None-the-less the diverse functions and cellular contexts of FcγR receptor expression ensure there is much still to understand of the protective and deleterious effects of FcγRs in HIV infection. Careful comparative studies of human and non-human primate FcγRs will facilitate our appreciation of what attributes of HIV specific IgG antibodies, either acquired naturally or via vaccination, are most important for protection.

  11. Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells

    PubMed Central

    Cong, Yu; McArthur, Monica A.; Cohen, Melanie; Jahrling, Peter B.; Janosko, Krisztina B.; Josleyn, Nicole; Kang, Kai; Zhang, Tengfei; Holbrook, Michael R.

    2016-01-01

    Humans infected with yellow fever virus (YFV), a mosquito-borne flavivirus, can develop illness ranging from a mild febrile disease to hemorrhagic fever and death. The 17D vaccine strain of YFV was developed in the 1930s, has been used continuously since development and has proven very effective. Genetic differences between vaccine and wild-type viruses are few, yet viral or host mechanisms associated with protection or disease are not fully understood. Over the past 20 years, a number of cases of vaccine-associated disease have been identified following vaccination with 17D; these cases have been correlated with reduced immune status at the time of vaccination. Recently, several studies have evaluated T cell responses to vaccination in both humans and non-human primates, but none have evaluated the response to wild-type virus infection. In the studies described here, monocyte-derived macrophages (MDM) and dendritic cells (MoDC) from both humans and rhesus macaques were evaluated for their ability to support infection with either wild-type Asibi virus or the 17D vaccine strain and the host cytokine and chemokine response characterized. Human MoDC and MDM were also evaluated for their ability to stimulate CD4+ T cells. It was found that MoDC and MDM supported viral replication and that there were differential cytokine responses to infection with either wild-type or vaccine viruses. Additionally, MoDCs infected with live 17D virus were able to stimulate IFN-γ and IL-2 production in CD4+ T cells, while cells infected with Asibi virus were not. These data demonstrate that wild-type and vaccine YFV stimulate different responses in target antigen presenting cells and that wild-type YFV can inhibit MoDC activation of CD4+ T cells, a critical component in development of protective immunity. These data provide initial, but critical insight into regulatory capabilities of wild-type YFV in development of disease. PMID:27191161

  12. HemaMax™, a Recombinant Human Interleukin-12, Is a Potent Mitigator of Acute Radiation Injury in Mice and Non-Human Primates

    PubMed Central

    Basile, Lena A.; Ellefson, Dolph; Gluzman-Poltorak, Zoya; Junes-Gill, Katiana; Mar, Vernon; Mendonca, Sarita; Miller, Joseph D.; Tom, Jamie; Trinh, Alice; Gallaher, Timothy K.

    2012-01-01

    HemaMax, a recombinant human interleukin-12 (IL-12), is under development to address an unmet medical need for effective treatments against acute radiation syndrome due to radiological terrorism or accident when administered at least 24 hours after radiation exposure. This study investigated pharmacokinetics, pharmacodynamics, and efficacy of m-HemaMax (recombinant murine IL-12), and HemaMax to increase survival after total body irradiation (TBI) in mice and rhesus monkeys, respectively, with no supportive care. In mice, m-HemaMax at an optimal 20 ng/mouse dose significantly increased percent survival and survival time when administered 24 hours after TBI between 8–9 Gy (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by increases in plasma interferon-γ (IFN-γ) and erythropoietin levels, recovery of femoral bone hematopoiesis characterized with the presence of IL-12 receptor β2 subunit–expressing myeloid progenitors, megakaryocytes, and osteoblasts. Mitigation of jejunal radiation damage was also examined. At allometrically equivalent doses, HemaMax showed similar pharmacokinetics in rhesus monkeys compared to m-HemaMax in mice, but more robustly increased plasma IFN-γ levels. HemaMax also increased plasma erythropoietin, IL-15, IL-18, and neopterin levels. At non-human primate doses pharmacologically equivalent to murine doses, HemaMax (100 ng/Kg and 250 ng/Kg) administered at 24 hours after TBI (6.7 Gy/LD50/30) significantly increased percent survival of HemaMax groups compared to vehicle (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by a significantly higher leukocyte (neutrophils and lymphocytes), thrombocyte, and reticulocyte counts during nadir (days 12–14) and significantly less weight loss at day 12 compared to vehicle. These findings indicate successful interspecies dose conversion and provide proof of concept that HemaMax increases survival in irradiated rhesus monkeys by promoting

  13. Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events

    PubMed Central

    Menon, Naresh; Rogers, Claude J.; Lukaszewicz, Agnes I.; Axtelle, James; Yadav, Marshleen; Song, Feifei; Chakravarti, Arnab; Jacob, Naduparambil K.

    2016-01-01

    Development of biomarkers capable of estimating absorbed dose is critical for effective triage of affected individuals after radiological events. Levels of cell-free circulating miRNAs in plasma were compared for dose-response analysis in non-human primates (NHP) exposed to lethal (6.5 Gy) and sub-lethal (1 and 3 Gy) doses over a 7 day period. The doses and test time points were selected to mimic triage needs in the event of a mass casualty radiological event. Changes in miRNA abundance in irradiated animals were compared to a non-irradiated cohort and a cohort experiencing acute inflammation response from exposure to lipopolysaccharide (LPS). An amplification-free, hybridization-based direct digital counting method was used for evaluation of changes in microRNAs in plasma from all animals. Consistent with previous murine studies, circulating levels of miR-150-5p exhibited a dose- and time-dependent decrease in plasma. Furthermore, plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics. Additionally, plasma levels of several other evolutionarily and functionally conserved miRNAs were found altered as a function of dose and time. Interestingly, miR-574-5p exhibited a distinct, dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure before returning to the baseline level by day 3. This particular miRNA response was not detected in previous murine studies but was observed in animals exposed to LPS, indicating distinct molecular and inflammatory responses. Furthermore, an increase in low-abundant miR-126, miR-144, and miR-21 as well as high-abundant miR-1-3p and miR-206 was observed in irradiated animals on day 3 and/or day 7. The data from this study could be used to develop a multi-marker panel with known tissue-specific origin that could be used for developing rapid assays for dose assessment and evaluation of radiation injury on multiple organs. Furthermore this approach may be

  14. Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells.

    PubMed

    Cong, Yu; McArthur, Monica A; Cohen, Melanie; Jahrling, Peter B; Janosko, Krisztina B; Josleyn, Nicole; Kang, Kai; Zhang, Tengfei; Holbrook, Michael R

    2016-05-01

    Humans infected with yellow fever virus (YFV), a mosquito-borne flavivirus, can develop illness ranging from a mild febrile disease to hemorrhagic fever and death. The 17D vaccine strain of YFV was developed in the 1930s, has been used continuously since development and has proven very effective. Genetic differences between vaccine and wild-type viruses are few, yet viral or host mechanisms associated with protection or disease are not fully understood. Over the past 20 years, a number of cases of vaccine-associated disease have been identified following vaccination with 17D; these cases have been correlated with reduced immune status at the time of vaccination. Recently, several studies have evaluated T cell responses to vaccination in both humans and non-human primates, but none have evaluated the response to wild-type virus infection. In the studies described here, monocyte-derived macrophages (MDM) and dendritic cells (MoDC) from both humans and rhesus macaques were evaluated for their ability to support infection with either wild-type Asibi virus or the 17D vaccine strain and the host cytokine and chemokine response characterized. Human MoDC and MDM were also evaluated for their ability to stimulate CD4+ T cells. It was found that MoDC and MDM supported viral replication and that there were differential cytokine responses to infection with either wild-type or vaccine viruses. Additionally, MoDCs infected with live 17D virus were able to stimulate IFN-γ and IL-2 production in CD4+ T cells, while cells infected with Asibi virus were not. These data demonstrate that wild-type and vaccine YFV stimulate different responses in target antigen presenting cells and that wild-type YFV can inhibit MoDC activation of CD4+ T cells, a critical component in development of protective immunity. These data provide initial, but critical insight into regulatory capabilities of wild-type YFV in development of disease.

  15. A collection of non-human primate computed tomography scans housed in MorphoSource, a repository for 3D data

    PubMed Central

    Copes, Lynn E.; Lucas, Lynn M.; Thostenson, James O.; Hoekstra, Hopi E.; Boyer, Doug M.

    2016-01-01

    A dataset of high-resolution microCT scans of primate skulls (crania and mandibles) and certain postcranial elements was collected to address questions about primate skull morphology. The sample consists of 489 scans taken from 431 specimens, representing 59 species of most Primate families. These data have transformative reuse potential as such datasets are necessary for conducting high power research into primate evolution, but require significant time and funding to collect. Similar datasets were previously only available to select research groups across the world. The physical specimens are vouchered at Harvard’s Museum of Comparative Zoology. The data collection took place at the Center for Nanoscale Systems at Harvard. The dataset is archived on MorphoSource.org. Though this is the largest high fidelity comparative dataset yet available, its provisioning on a web archive that allows unlimited researcher contributions promises a future with vastly increased digital collections available at researchers’ finger tips. PMID:26836025

  16. Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and αDEC-CSP in Non Human Primates

    PubMed Central

    Tewari, Kavita; Flynn, Barbara J.; Boscardin, Silvia B.; Kastenmueller, Kathrin; Salazar, Andres M.; Anderson, Charles A.; Soundarapandian, Velu; Ahumada, Adriana; Keler, Tibor; Hoffman, Stephen L.; Nussenzweig, Michel C.; Steinman, Ralph M.; Seder, Robert A.

    2010-01-01

    Development of a fully effective vaccine against the pre-erythrocytic stage of malaria infection will likely require induction of both humoral and cellular immune responses. Protein based vaccines can elicit such broad-based immunity depending on the adjuvant and how the protein is formulated. Here to assess these variables, non-human primates (NHP) were immunized three times with Plasmodium falciparum (Pf) circumsporozoite protein (CSP) or CSP cloned into MG38, a monoclonal antibody that targets DEC-205 (αDEC-CSP), an endocytic receptor on dendritic cells (DCs). Both vaccines were administered with or without poly(I:C) as adjuvant. Following three immunizations, the magnitude and quality of cytokine secreting CD4+ T cells were comparable between CSP + poly(I:C) and αDEC-CSP + poly(I:C) groups with both regimens eliciting multi-functional cytokine responses. However, NHP immunized with CSP + poly(I:C) had significantly higher serum titers of CSP-specific IgG antibodies and indirect immunofluorescent antibody (IFA) titers against Pf sporozoites. Furthermore, sera from both CSP or αDEC-CSP + poly(I:C) immunized animals limited sporozoite invasion of a hepatocyte cell line (HC04) in vitro. To determine whether CSP-specific responses could be enhanced, all NHP primed with CSP or αDEC-CSP + poly(I:C) were boosted with a single dose of 150,000 irradiated Pf sporozoites (PfSPZ) intravenously. Remarkably, boosting had no effect on the CSP-specific immunity. Finally, immunization with CSP + poly-ICLC reduced malaria parasite burden in the liver in an experimental mouse model. Taken together, these data showing that poly(I:C) is an effective adjuvant for inducing potent antibody and Th1 immunity with CSP based vaccines offers a potential alternative to the existing protein based pre-erythrocytic vaccines. PMID:20846528

  17. Primate polonium metabolic models and their use in estimation of systemic radiation doses from bioassay data

    SciTech Connect

    Fellman, A.

    1989-01-01

    A Polonium metabolic model was derived and incorporated into a Fortran algorithm which estimates the systemic radiation dose from {sup 210}Po when applied to occupational urine bioassay data. The significance of the doses estimated are examined by defining the degree of uncertainty attached to them through comprehensive statistical testing procedures. Many parameters necessary for dosimetry calculations, were evaluated from metabolic studies of {sup 210}Po in non-human primates. Two tamarins and six baboons were injected intravenously with {sup 210}Po citrate. Excreta and blood samples were collected. Five of the baboons were sacrifice at times ranging from 1 day to 3 months post exposure. Complete necropsies were performed and all excreta and the majority of all skeletal and tissue samples were analyzed radiochemically for their {sup 210}Po content. The {sup 210}Po excretion rate in the baboon was more rapid than in the tamarin. The biological half-time of {sup 210}Po excretion in the baboon was approximately 15 days while in the tamarin, the {sup 210}Po excretion rate was in close agreement with the 50 day biological half-time predicted by ICRP 30. Excretion fractions of {sup 210}Po in the non-human primates were found to be markedly different from data reported elsewhere in other species, including man.

  18. Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease

    PubMed Central

    Mattoso-Barbosa, Armanda Moreira; Perdigão-de-Oliveira, Marcelo; Costa, Ronaldo Peres; Elói-Santos, Silvana Maria; Gomes, Matheus de Souza; do Amaral, Laurence Rodrigues; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Dick, Edward J.; Hubbard, Gene B.; VandeBerg, Jane F.; VandeBerg, John L.

    2016-01-01

    Background Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations. Methods and Findings Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications. Conclusions Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease. PMID:26808481

  19. Integrated Safety Assessment of 2′-O-Methoxyethyl Chimeric Antisense Oligonucleotides in NonHuman Primates and Healthy Human Volunteers

    PubMed Central

    Crooke, Stanley T; Baker, Brenda F; Kwoh, T Jesse; Cheng, Wei; Schulz, Dan J; Xia, Shuting; Salgado, Nelson; Bui, Huynh-Hoa; Hart, Christopher E; Burel, Sebastien A; Younis, Husam S; Geary, Richard S; Henry, Scott P; Bhanot, Sanjay

    2016-01-01

    The common chemical and biological properties of antisense oligonucleotides provide the opportunity to identify and characterize chemical class effects across species. The chemical class that has proven to be the most versatile and best characterized is the 2′-O-methoxyethyl chimeric antisense oligonucleotides. In this report we present an integrated safety assessment of data obtained from controlled dose-ranging studies in nonhuman primates (macaques) and healthy human volunteers for 12 unique 2′-O-methoxyethyl chimeric antisense oligonucleotides. Safety was assessed by the incidence of safety signals in standardized laboratory tests for kidney and liver function, hematology, and complement activation; as well as by the mean test results as a function of dose level over time. At high doses a number of toxicities were observed in nonhuman primates. However, no class safety effects were identified in healthy human volunteers from this integrated data analysis. Effects on complement in nonhuman primates were not observed in humans. Nonhuman primates predicted safe doses in humans, but over predicted risk of complement activation and effects on platelets. Although limited to a single chemical class, comparisons from this analysis are considered valid and accurate based on the carefully controlled setting for the specified study populations and within the total exposures studied. PMID:27357629

  20. Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research

    PubMed Central

    Ponte, Rosalie; Mehraj, Vikram; Ghali, Peter; Couëdel-Courteille, Anne; Cheynier, Rémi; Routy, Jean-Pierre

    2016-01-01

    Antiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV-infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity. PMID:26981570

  1. Novel Serum Proteomic Signatures in a Non-Human Primate Model of Retinal Injury

    DTIC Science & Technology

    2011-01-01

    photoreceptors [50] and PGK1 deficiency has been implicated in one case of retinitis pigmentosa [51]. It is likely this enzyme is abundant in metabolically...DB=tr 2 3 2 1 0.234633 0.218250 Q4G3V7 KIAA0476 (Fragment) OS=Macaca mulatta PE=2 SV=1 DB=tr 2 3 2 1 0.234633 0.218250 Q4G413 Retinitis pigmentosa 1...4.070046 0.142449 Q4G413 Retinitis pigmentosa 1 (Fragment) OS=Macaca mulatta GN=RP1 PE=2 SV=1 DB=tr 5 6 1 4 4.070046 0.142449 Q6IYG8 NADH-ubiquinone

  2. Study of the role of novel RF-amide neuropeptides in affecting growth hormone secretion in a representative non-human primate (Macaca mulatta).

    PubMed

    Qaiser, Fatima; Wahab, Fazal; Wiqar, Muhammad Amin; Hashim, Rizwan; Leprince, Jerome; Vaudry, Hubert; Tena-Sempere, Manuel; Shahab, Muhammad

    2012-12-01

    RF amide peptide family with distinctive terminal -Arg-Phe-NH(2) signature is evolutionarily conserved from invertebrates to mammals. These neuropeptides have been shown to affect diverse functions in invertebrates and vertebrates including influencing pituitary hormone secretion. More recently, two members of this family 26-amino acid and 43-amino acid RF amide peptide (26RFa and 43RFa, respectively) originally isolated from frog have been cloned in rats and humans. Actions of these peptides on hormone secretion have not been studied in primates. In the present study, effect of iv administration of three different doses of human 26RFa and 43RFa on GH secretion was studied in a representative higher primate, the rhesus monkey. As control against these two peptides, normal saline and a scrambled sequence of 26RFa was administered. A set of four intact adult male monkeys received the administration in a random order. Peripheral blood samples were obtained from the chairrestrained but fully conscious animals for a period of 30 min before and 240 min after the administration at 15-min intervals. For quantitative measurement of GH concentration, a human GH chemiluminescent immunometric assay was used. Peripheral administration of 38 and 76 nmol doses of 26RFa significantly (P < 0.05) stimulated GH AUC during a 0-120 min period after injection of 26RFa. In contrast to 26RFa, administration of 43RFa appeared to suppress GH levels during the later stages of the sampling i.e. from 120 to 240 min period. Mean AUC during the period was significantly (P < 0.05) reduced by 76 nmol dose of 43RFa, while 38 nmol dose of 43RFa also had similar effect but lacked full statistical significance (P = 0.058). To our knowledge present study reports for the first time-specific stimulatory effect of 26RFa on the GH secretion and a novel inhibitory and delayed effect of 43RFa on the GH secretion in higher primates. In conclusion, present findings extend evidence for endocrine actions of RF

  3. Chikungunya antibodies detected in non-human primates and rats in three Indian Ocean islands after the 2006 ChikV outbreak

    PubMed Central

    2014-01-01

    The role of terrestrial vertebrates in the epidemiology of chikungunya disease is poorly understood. We evaluated their exposure and amplification role during the 2006 chikungunya outbreak in the Indian Ocean. Blood samples were collected from 18 mammalian and reptile species from Reunion Island, Mauritius and Mayotte. Among the 1051 samples serologically tested for chikungunya virus (CHIKV), two crab-eating macaques (Macaca fascicularis) and two ship rats (Rattus rattus) proved to be exposed to CHIKV. CHIKV RNA was not detected in 791 analyzed sera. Our results confirm the preferential infection of simian primates and suggest that other vertebrates played a poor or no role in CHIKV transmission during the 2006 outbreak. PMID:24885529

  4. Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing.

    PubMed

    O'Neil, Richard T; Wang, Xiaojing; Morabito, Michael V; Emeson, Ronald B

    2017-04-06

    A-to-I RNA editing is an important process for generating molecular diversity in the brain through modification of transcripts encoding several proteins important for neuronal signaling. We investigated the relationships between the extent of editing at multiple substrate transcripts (5HT2C, MGLUR4, CADPS, GLUR2, GLUR4, and GABRA3) in brain tissue obtained from adult humans and rhesus macaques. Several patterns emerged from these studies revealing conservation of editing across primate species. Additionally, variability in the human population allows us to make novel inferences about the co-regulation of editing at different editing sites and even across different brain regions.

  5. An analytical model for calculating internal dose conversion coefficients for non-human biota.

    PubMed

    Amato, Ernesto; Italiano, Antonio

    2014-05-01

    To assess the radiation burden of non-human living organisms, dose coefficients are available in the literature, precalculated by assuming an ellipsoidal shape of each organism. A previously developed analytical method was applied for the determination of absorbed fractions inside ellipsoidal volumes from alpha, beta, and gamma radiations to the calculation of dose conversion coefficients (DCCs) for 15 reference organisms, animals and plants, either terrestrial, amphibian, or aquatic, and six radionuclides ((14)C, (90)Sr, (60)Co, (137)Cs, (238)U, and (241)Am). The results were compared with the reference values reported in Publication 108 of the International Commission on Radiological Protection, in which a different calculation approach for DCCs was employed. The results demonstrate that the present analytical method, originally intended for applications in internal dosimetry of nuclear medicine therapy, gives consistent results for all the beta-, beta-gamma-, and alpha-emitting radionuclides tested in a wide range of organism masses, between 8 mg and 1.3 kg. The applicability of the method proposed can take advantage from its ease of implementation in an ordinary electronic spreadsheet, allowing to calculate, for virtually all possible radionuclide emission spectra, the DCCs for ellipsoidal models of non-human living organisms in the environment.

  6. Diversity and prevalence of gastrointestinal parasites in seven non-human primates of the Taï National Park, Côte d’Ivoire

    PubMed Central

    Kouassi, Roland Yao Wa; McGraw, Scott William; Yao, Patrick Kouassi; Abou-Bacar, Ahmed; Brunet, Julie; Pesson, Bernard; Bonfoh, Bassirou; N’goran, Eliezer Kouakou; Candolfi, Ermanno

    2015-01-01

    Parasites and infectious diseases are well-known threats to primate populations. The main objective of this study was to provide baseline data on fecal parasites in the cercopithecid monkeys inhabiting Côte d’Ivoire’s Taï National Park. Seven of eight cercopithecid species present in the park were sampled: Cercopithecus diana, Cercopithecus campbelli, Cercopithecus petaurista, Procolobus badius, Procolobus verus, Colobus polykomos, and Cercocebus atys. We collected 3142 monkey stool samples between November 2009 and December 2010. Stool samples were processed by direct wet mount examination, formalin-ethyl acetate concentration, and MIF (merthiolate, iodine, formalin) concentration methods. Slides were examined under microscope and parasite identification was based on the morphology of cysts, eggs, and adult worms. A total of 23 species of parasites was recovered including 9 protozoa (Entamoeba coli, Entamoeba histolytica/dispar, Entamoeba hartmanni, Endolimax nana, Iodamoeba butschlii, Chilomastix mesnili, Giardia sp., Balantidium coli, and Blastocystis sp.), 13 nematodes (Oesophagostomum sp., Ancylostoma sp., Anatrichosoma sp., Capillariidae Gen. sp. 1, Capillariidae Gen. sp. 2, Chitwoodspirura sp., Subulura sp., spirurids [cf Protospirura muricola], Ternidens sp., Strongyloides sp., Trichostrongylus sp., and Trichuris sp.), and 1 trematode (Dicrocoelium sp.). Diversity indices and parasite richness were high for all monkey taxa, but C. diana, C. petaurista, C. atys, and C. campbelli exhibited a greater diversity of parasite species and a more equitable distribution. The parasitological data reported are the first available for these cercopithecid species within Taï National Park. PMID:25619957

  7. The development of small primate models for aging research.

    PubMed

    Fischer, Kathleen E; Austad, Steven N

    2011-01-01

    Nonhuman primate (NHP) aging research has traditionally relied mainly on the rhesus macaque. But the long lifespan, low reproductive rate, and relatively large body size of macaques and related Old World monkeys make them less than ideal models for aging research. Manifold advantages would attend the use of smaller, more rapidly developing, shorter-lived NHP species in aging studies, not the least of which are lower cost and the ability to do shorter research projects. Arbitrarily defining "small" primates as those weighing less than 500 g, we assess small, relatively short-lived species among the prosimians and callitrichids for suitability as models for human aging research. Using the criteria of availability, knowledge about (and ease of) maintenance, the possibility of genetic manipulation (a hallmark of 21st century biology), and similarities to humans in the physiology of age-related changes, we suggest three species--two prosimians (Microcebus murinus and Galago senegalensis) and one New World monkey (Callithrix jacchus)--that deserve scrutiny for development as major NHP models for aging studies. We discuss one other New World monkey group, Cebus spp., that might also be an effective NHP model of aging as these species are longer-lived for their body size than any primate except humans.

  8. Pu-239 organ specific dosimetric model applied to non-human biota

    NASA Astrophysics Data System (ADS)

    Kaspar, Matthew Jason

    There are few locations throughout the world, like the Maralinga nuclear test site located in south western Australia, where sufficient plutonium contaminate concentration levels exist that they can be utilized for studies of the long-term radionuclide accumulation in non-human biota. The information obtained will be useful for the potential human users of the site while also keeping with international efforts to better understand doses to non-human biota. In particular, this study focuses primarily on a rabbit sample set collected from the population located within the site. Our approach is intended to employ the same dose and dose rate methods selected by the International Commission on Radiological Protection and adapted by the scientific community for similar research questions. These models rely on a series of simplifying assumptions on biota and their geometry; in particular; organisms are treated as spherical and ellipsoidal representations displaying the animal mass and volume. These simplifications assume homogeneity of all animal tissues. In collaborative efforts between Colorado State University and the Australian Nuclear Science and Technology Organisation (ANSTO), we are expanding current knowledge on radionuclide accumulation in specific organs causing organ-specific dose rates, such as Pu-239 accumulating in bone, liver, and lungs. Organ-specific dose models have been developed for humans; however, little has been developed for the dose assessment to biota, in particular rabbits. This study will determine if it is scientifically valid to use standard software, in particular ERICA Tool, as a means to determine organ-specific dosimetry due to Pu-239 accumulation in organs. ERICA Tool is normally applied to whole organisms as a means to determine radiological risk to whole ecosystems. We will focus on the aquatic model within ERICA Tool, as animal organs, like aquatic organisms, can be assumed to lie within an infinite uniform medium. This model would

  9. Animal models for prenatal gene therapy: the nonhuman primate model.

    PubMed

    Mattar, Citra N; Biswas, Arijit; Choolani, Mahesh; Chan, Jerry K Y

    2012-01-01

    Intrauterine gene therapy (IUGT) potentially enables the treatment and possible cure of monogenic -diseases that cause severe fetal damage. The main benefits of this approach will be the ability to correct the disorder before the onset of irreversible pathology and inducing central immune tolerance to the vector and transgene if treatment is instituted in early gestation. Cure has been demonstrated in small animal models, but because of the significant differences in immune ontogeny and the much shorter gestation compared to humans, it is unlikely that questions of long-term efficacy and safety will be adequately addressed in rodents. The nonhuman primate (NHP) allows investigation of key issues, in particular, the different outcomes in early and late-gestation IUGT associated with different stages of immune maturity, longevity of transgene expression, and delayed-onset adverse events in treated offspring and mothers including insertional mutagenesis. Here, we describe a model based on the Macaca fascicularis using ultrasound and fetoscopic approaches to systemic vector delivery and the processes involved in vector administration and longitudinal analyses.

  10. Recovering stimulus locations using populations of eye-position modulated neurons in dorsal and ventral visual streams of non-human primates

    PubMed Central

    Sereno, Anne B.; Sereno, Margaret E.; Lehky, Sidney R.

    2014-01-01

    We recorded visual responses while monkeys fixated the same target at different gaze angles, both dorsally (lateral intraparietal cortex, LIP) and ventrally (anterior inferotemporal cortex, AIT). While eye-position modulations occurred in both areas, they were both more frequent and stronger in LIP neurons. We used an intrinsic population decoding technique, multidimensional scaling (MDS), to recover eye positions, equivalent to recovering fixated target locations. We report that eye-position based visual space in LIP was more accurate (i.e., metric). Nevertheless, the AIT spatial representation remained largely topologically correct, perhaps indicative of a categorical spatial representation (i.e., a qualitative description such as “left of” or “above” as opposed to a quantitative, metrically precise description). Additionally, we developed a simple neural model of eye position signals and illustrate that differences in single cell characteristics can influence the ability to recover target position in a population of cells. We demonstrate for the first time that the ventral stream contains sufficient information for constructing an eye-position based spatial representation. Furthermore we demonstrate, in dorsal and ventral streams as well as modeling, that target locations can be extracted directly from eye position signals in cortical visual responses without computing coordinate transforms of visual space. PMID:24734008

  11. Modeling the biomechanics of articular eminence function in anthropoid primates.

    PubMed

    Terhune, Claire E

    2011-11-01

    One of the most prominent features of the cranial component of the temporomandibular joint (TMJ) is the articular eminence (AE). This bar of bone is the primary surface upon which the condyle translates and rotates during movements of the mandible, and is therefore the primary point at which forces are transmitted from the mandible to the cranium during loading of the masticatory apparatus. The shape of the AE is highly variable across primates, and the raised eminence of humans has often been considered a defining feature of the human TMJ, yet few data exist to address whether this variation is functionally significant. This study used a broad interspecific sample of anthropoid primates to elaborate upon and test the predictions of a previously proposed model of AE function. This model suggests that AE inclination acts to resist non-normal forces at the TMJ, thereby maximizing bite forces (BFs). AE inclination was predicted to covary with two specific features of the masticatory apparatus: height of the TMJ above the occlusal plane; and inclination of the masticatory muscles. A correlate of this model is that taxa utilizing more resistant food objects should also exhibit relatively more inclined AEs. Results of the correlation analyses found that AE inclination is strongly correlated with height of the TMJ above the occlusal plane, but less so with inclination of the masticatory muscles. Furthermore, pairwise comparisons of closely related taxa with documented dietary differences found that the AE is consistently more inclined in taxa that utilize more resistant food items. These data preliminarily suggest that variation in AE morphology across anthropoid primates is functionally related to maximizing BFs, and add to the growing dataset of masticatory morphologies linked to feeding behavior.

  12. Evaluation of [18F]-(−)-Norchlorofluorohomoepibatidine ([18F]-(−)-NCFHEB) as a PET Radioligand to Image the Nicotinic Acetylcholine Receptors in Non-human Primates

    PubMed Central

    Bois, Frederic; Gallezot, Jean-Dominique; Zheng, Ming-Qiang; Lin, Shu-Fei; Esterlis, Irina; Cosgrove, Kelly P.; Carson, Richard E.; Huang, Yiyun

    2015-01-01

    Introduction The aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine α4β2 receptor radiotracer [18F]-(−)-NCFHEB ([18F]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo. Methods [18F]-(−)-NCFHEB was prepared in two steps, a nucleophilic fluorination followed by N-Boc deprotection. PET measurements were performed in rhesus monkeys including baseline and preblocking experiments with nicotine (0.24 mg/kg). Radiometabolites in plasma were measured using HPLC. Results [18F]-(−)-NCFHEB was prepared in a total synthesis time of 140 min. The radiochemical purity in its final formulation was >98% and the mean specific radioactivity was 97.3 ± 16.1Bq/μmol (n = 6) at end of synthesis (EOS). In the monkey brain, radioactivity concentration was high in the thalamus, moderate in the putamen, hippocampus, frontal cortex, and lower in the cerebellum. Nicotine blocked 98–100% of [18F]-(−)-NCFHEB specific binding, and the non-displaceable distribution volume (VND) was estimated at 5.9 ± 1.0 mL/cm3 (n = 2), or 6.6 ± 1.1 mL/cm3 after normalization by the plasma free fraction fP. Imaging data are amenable to kinetic modeling analysis using the multilinear analysis (MA1) method, and model-derived binding parameters display good test-retest reproducibility. In rhesus monkeys, [18F]-(−)-NCFHEB can yield robust regional binding potential (BPND) values (thalamus = 4.1 ± 1.5, frontal cortex = 1.2 ± 0.2, putamen = 0.96 ± 0.45, cerebellum = 0.10 ± 0.29). Conclusion An efficient microfluidic synthetic method was developed for preparation of [18F]-(−)-NCFHEB. PET examination in rhesus monkeys showed that [18F]-(−)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of α4β2 receptors. Estimated non-displaceable binding potential (BPND) values in brain

  13. Phenotypical and functional characterization of non-human primate Aotus spp. dendritic cells and their use as a tool for characterizing immune response to protein antigens.

    PubMed

    Gabriela, Delgado; Carlos, Parra-López; Clara, Spinel; Elkin, Patarroyo Manuel

    2005-05-16

    A population of cells exhibiting bona fide dendritic cell (DC) morphological and functional characteristics was obtained by treating Aotus spp. monocytes with human IL-4 and GM-CSF. Although the purity of mature DCs was relatively low IL-4/GM-CSF-treated monocytes (hereafter called Aotus spp. DCs) down-regulated CD14 and up-regulated discrete levels of CD80, MHC-Class II and CD1b molecules in response to different maturation stimuli. Aotus spp. DCs generated a potent allogeneic in vitro response evidenced in mixed lymphocyte reaction (MLR) where DCs were 2- to 10-fold more efficient than peripheral blood mononuclear cells (PBMCs). Aotus spp. DC ability to boost T-cells or priming naive T-cells in vivo was proved by vaccinating Aotus spp. with autologous DCs pulsed with tetanus toxoid (TT). A single dose of TT-pulsed DCs was sufficient to increase cellular response to TT in these experiments as assessed by lymphoproliferation and cytokine production. Since Aotus spp. represents a suitable animal model for evaluating anti-Plasmodium falciparum malaria vaccine, the results shown here suggest that using antigen-pulsed Aotus spp. DCs as vaccines might lead to identifying new prospects for malarial vaccines unidentified to date because they are being formulated in less efficient adjuvants.

  14. A Predictive Structural Model of the Primate Connectome

    PubMed Central

    Beul, Sarah F.; Barbas, Helen; Hilgetag, Claus C.

    2017-01-01

    Anatomical connectivity imposes strong constraints on brain function, but there is no general agreement about principles that govern its organization. Based on extensive quantitative data, we tested the power of three factors to predict connections of the primate cerebral cortex: architectonic similarity (structural model), spatial proximity (distance model) and thickness similarity (thickness model). Architectonic similarity showed the strongest and most consistent influence on connection features. This parameter was strongly associated with the presence or absence of inter-areal connections and when integrated with spatial distance, the factor allowed predicting the existence of projections with very high accuracy. Moreover, architectonic similarity was strongly related to the laminar pattern of projection origins, and the absolute number of cortical connections of an area. By contrast, cortical thickness similarity and distance were not systematically related to connection features. These findings suggest that cortical architecture provides a general organizing principle for connections in the primate brain, providing further support for the well-corroborated structural model. PMID:28256558

  15. Pathogenesis of varicelloviruses in primates.

    PubMed

    Ouwendijk, Werner J D; Verjans, Georges M G M

    2015-01-01

    Varicelloviruses in primates comprise the prototypic human varicella-zoster virus (VZV) and its non-human primate homologue, simian varicella virus (SVV). Both viruses cause varicella as a primary infection, establish latency in ganglionic neurons and reactivate later in life to cause herpes zoster in their respective hosts. VZV is endemic worldwide and, although varicella is usually a benign disease in childhood, VZV reactivation is a significant cause of neurological disease in the elderly and in immunocompromised individuals. The pathogenesis of VZV infection remains ill-defined, mostly due to the species restriction of VZV that impedes studies in experimental animal models. SVV infection of non-human primates parallels virological, clinical, pathological and immunological features of human VZV infection, thereby providing an excellent model to study the pathogenesis of varicella and herpes zoster in its natural host. In this review, we discuss recent studies that provided novel insight in both the virus and host factors involved in the three elementary stages of Varicellovirus infection in primates: primary infection, latency and reactivation.

  16. Dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rodents, pigs, non-human primates and human - repeated scanning in human is possible.

    PubMed

    Selvaraju, Ram Kumar; Bulenga, Thomas N; Espes, Daniel; Lubberink, Mark; Sörensen, Jens; Eriksson, Barbro; Estrada, Sergio; Velikyan, Irina; Eriksson, Olof

    2015-01-01

    Quantitative PET imaging with [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has potential use in diabetes and cancer. However, the radiation dose to the kidneys has been a concern for the possibility of repeated imaging studies in humans. Therefore, we investigated the dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 based on the biodistribution data in rats, pigs, non-human primates (NHP) and a human.Organ distribution of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rats (Male Lewis; n=12; 30, 60, and 80 min) was measured ex vivo. The dynamic uptake of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in the abdomen was assessed by PET/CT scanning of pigs (male; n = 4, 0-60 min), NHP (Female; cynomolgus; n=3; 0-90 min), and human (female; n=1; 0-40, 100, 120 min).The organ distribution data in each species were extrapolated to those of a human, assuming similar distribution between the species. Residence times were assessed by trapezoidal approximation of the kinetic data. Organ doses (mGy/MBq) and the whole body effective dose (mSv/MBq), was extrapolated by using the OLINDA/EXM 1.1 software. The extrapolated human whole body effective dose was 0.017 ± 0.004 (rats), 0.014 ± 0.004 (pigs), 0.017 ± 0.004 (NHP), and 0.016 (human) mSv/MBq. The absorbed dose to the kidneys was limiting:0.33 ± 0.06 (rats), 0.28±0.05 (pigs), 0.65 ± 0.11 (NHP), and 0.28 (human) mGy/MBq, which corresponded to the maximum yearly administered amounts of 455 (rat), 536 (pig), 231 (NHP), and 536 (human) MBq before reaching the yearly kidney limiting dose of 150 mGy. More than 200 MBq of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 can be administered yearly in a human, allowing for repeated (2-4 times) scanning. This potentially enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma.

  17. Induction of protective immunity against H1N1 influenza A(H1N1)pdm09 with spray-dried and electron-beam sterilised vaccines in non-human primates.

    PubMed

    Scherließ, Regina; Ajmera, Ankur; Dennis, Mike; Carroll, Miles W; Altrichter, Jens; Silman, Nigel J; Scholz, Martin; Kemter, Kristina; Marriott, Anthony C

    2014-04-17

    Currently, the need for cooled storage and the impossibility of terminal sterilisation are major drawbacks in vaccine manufacturing and distribution. To overcome current restrictions a preclinical safety and efficacy study was conducted to evaluate new influenza A vaccine formulations regarding thermal resistance, resistance against irradiation-mediated damage and storage stability. We evaluated the efficacy of novel antigen stabilizing and protecting solutions (SPS) to protect influenza A(H1N1)pdm09 split virus antigen under experimental conditions in vitro and in vivo. Original or SPS re-buffered vaccine (Pandemrix) was spray-dried and terminally sterilised by irradiation with 25 kGy (e-beam). Antigen integrity was monitored by SDS-PAGE, dynamic light scattering, size exclusion chromatography and functional haemagglutination assays. In vitro screening experiments revealed a number of highly stable compositions containing glycyrrhizinic acid (GA) and/or chitosan. The most stable composition was selected for storage tests and in vivo assessment of seroconversion in non-human primates (Macaca fascicularis) using a prime-boost strategy. Redispersed formulations with original adjuvant were administered intramuscularly. Storage data revealed high stability of protected vaccines at 4°C and 25°C, 60% relative humidity, for at least three months. Animals receiving original Pandemrix exhibited expected levels of seroconversion after 21 days (prime) and 48 days (boost) as assessed by haemagglutination inhibition and microneutralisation assays. Animals vaccinated with spray-dried and irradiated Pandemrix failed to exhibit seroconversion after 21 days whereas spray-dried and irradiated, SPS-protected vaccines elicited similar seroconversion levels to those vaccinated with original Pandemrix. Boost immunisation with SPS-protected vaccine resulted in a strong increase in seroconversion but had only minor effects in animals treated with non SPS-protected vaccine. In conclusion

  18. On folivory, competition, and intelligence: generalisms, overgeneralizations, and models of primate evolution.

    PubMed

    Sayers, Ken

    2013-04-01

    Considerations of primate behavioral evolution often proceed by assuming the ecological and competitive milieus of particular taxa via their relative exploitation of gross food types, such as fruits versus leaves. Although this "fruit/leaf dichotomy" has been repeatedly criticized, it continues to be implicitly invoked in discussions of primate socioecology and female social relationships and is explicitly invoked in models of brain evolution. An expanding literature suggests that such views have severely limited our knowledge of the social and ecological complexities of primate folivory. This paper examines the behavior of primate folivore-frugivores, with particular emphasis on gray langurs (traditionally, Semnopithecus entellus) within the broader context of evolutionary ecology. Although possessing morphological characteristics that have been associated with folivory and constrained activity patterns, gray langurs are known for remarkable plasticity in ecology and behavior. Their diets are generally quite broad and can be discussed in relation to Liem's Paradox, the odd coupling of anatomical feeding specializations with a generalist foraging strategy. Gray langurs, not coincidentally, inhabit arguably the widest range of habitats for a nonhuman primate, including high elevations in the Himalayas. They provide an excellent focal point for examining the assumptions and predictions of behavioral, socioecological, and cognitive evolutionary models. Contrary to the classical descriptions of the primate folivore, Himalayan and other gray langurs-and, in actuality, many leaf-eating primates-range widely, engage in resource competition (both of which have previously been noted for primate folivores), and solve ecological problems rivaling those of more frugivorous primates (which has rarely been argued for primate folivores). It is maintained that questions of primate folivore adaptation, temperate primate adaptation, and primate evolution more generally cannot be

  19. Primate polonium metabolic models and their use in estimation of systemic radiation doses from bioassay data. Final report

    SciTech Connect

    Cohen, N.

    1989-03-15

    A Polonium metabolic model was derived and incorporated into a Fortran algorithm which estimates the systemic radiation dose from {sup 210}Po when applied to occupational urine bioassay data. The significance of the doses estimated are examined by defining the degree of uncertainty attached to them through comprehensive statistical testing procedures. Many parameters necessary for dosimetry calculations (such as organ partition coefficients and excretion fractions), were evaluated from metabolic studies of {sup 210}Po in non-human primates. Two tamarins and six baboons were injected intravenously with {sup 210}Po citrate. Excreta and blood samples were collected. Five of the baboons were sacrificed at times ranging from 1 day to 3 months post exposure. Complete necropsies were performed and all excreta and the majority of all skeletal and tissue samples were analyzed radiochemically for their {sup 210}Po content. The {sup 210}Po excretion rate in the baboon was more rapid than in the tamarin. The biological half-time of {sup 210}Po excretion in the baboon was approximately 15 days while in the tamarin, the {sup 210}Po excretion rate was in close agreement with the 50 day biological half-time predicted by ICRP 30. Excretion fractions of {sup 210}Po in the non-human primates were found to be markedly different from data reported elsewhere in other species, including man. A thorough review of the Po urinalysis procedure showed that significant recovery losses resulted when metabolized {sup 210}Po was deposited out of raw urine. Polonium-210 was found throughout the soft tissues of the baboon but not with the partition coefficients for liver, kidneys, and spleen that are predicted by the ICRP 30 metabolic model. A fractional distribution of 0.29 for liver, 0.07 for kidneys, and 0.006 for spleen was determined. Retention times for {sup 210}Po in tissues are described by single exponential functions with biological half-times ranging from 15 to 50 days.

  20. On folivory, competition, and intelligence: generalism, overgeneralizations, and models of primate evolution

    PubMed Central

    Sayers, Ken

    2013-01-01

    Considerations of primate behavioral evolution often proceed by assuming the ecological and competitive milieus of particular taxa via their relative exploitation of gross food types, such as fruits versus leaves. Although this “fruit/leaf dichotomy” has been repeatedly criticized, it continues to be implicitly invoked in discussions of primate socioecology and female social relationships, and explicitly invoked in models of brain evolution. An expanding literature suggests that such views have severely limited our knowledge of the social and ecological complexities of primate folivory. This paper examines the behavior of primate folivore-frugivores, with particular emphasis on gray langurs (traditionally, Semnopithecus entellus) within the broader context of evolutionary ecology. Although possessing morphological characters that have been associated with folivory and constrained activity patterns, gray langurs are known for remarkable plasticity in ecology and behavior. Their diets are generally quite broad and can be discussed in relation to “Liem’s paradox,” the odd coupling of anatomical feeding specializations with a generalist foraging strategy. Gray langurs, not coincidentally, inhabit arguably the widest range of habitats for a nonhuman primate, including high elevations in the Himalayas. They provide an excellent focal point for examining the assumptions and predictions of behavioral, socioecological, and cognitive evolutionary models. Contrary to the classical descriptions of the primate folivore, Himalayan and other gray langurs—and, in actuality, many leaf eating primates—range widely and engage in resource competition (both of which have previously been noted for primate folivores) as well as solve ecological problems rivaling those of more frugivorous primates (which has rarely been argued for primate folivores). It is maintained that questions of primate folivore adaptation, temperate primate adaptation, and primate evolution more

  1. Nonhuman primate model of schizophrenia using a noninvasive EEG method

    PubMed Central

    Gil-da-Costa, Ricardo; Stoner, Gene R.; Fung, Raynard; Albright, Thomas D.

    2013-01-01

    There is growing evidence that impaired sensory-processing significantly contributes to the cognitive deficits found in schizophrenia. For example, the mismatch negativity (MMN) and P3a event-related potentials (ERPs), neurophysiological indices of sensory and cognitive function, are reduced in schizophrenia patients and may be used as biomarkers of the disease. In agreement with glutamatergic theories of schizophrenia, NMDA antagonists, such as ketamine, elicit many symptoms of schizophrenia when administered to normal subjects, including reductions in the MMN and the P3a. We sought to develop a nonhuman primate (NHP) model of schizophrenia based on NMDA-receptor blockade using subanesthetic administration of ketamine. This provided neurophysiological measures of sensory and cognitive function that were directly comparable to those recorded from humans. We first developed methods that allowed recording of ERPs from humans and rhesus macaques and found homologous MMN and P3a ERPs during an auditory oddball paradigm. We then investigated the effect of ketamine on these ERPs in macaques. As found in humans with schizophrenia, as well as in normal subjects given ketamine, we observed a significant decrease in amplitude of both ERPs. Our findings suggest the potential of a pharmacologically induced model of schizophrenia in NHPs that can pave the way for EEG-guided investigations into cellular mechanisms and therapies. Furthermore, given the established link between these ERPs, the glutamatergic system, and deficits in other neuropsychiatric disorders, our model can be used to investigate a wide range of pathologies. PMID:23959894

  2. Establishment of a Non-human Primate Campylobacter Disease Model for the Pre-clinical Evaluation of Campylobacter Vaccine Formulations

    DTIC Science & Technology

    2005-07-25

    c, Daniel Scott c, Carl J. Mason a a Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), 315/6 Rajvithi...Road, Bangkok 10400, Thailand b Department of Veterinary Medicine, AFRIMS, Bangkok, Thailand c Naval Medical Research Center (NMRC), Silver Spring, MD...Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), 315/6 Rajvithi Road, Bangkok 10400, Thailand 8

  3. Insights into an Optimization of Plasmodium vivax Sal-1 In Vitro Culture: The Aotus Primate Model.

    PubMed

    Shaw-Saliba, Kathryn; Thomson-Luque, Richard; Obaldía, Nicanor; Nuñez, Marlon; Dutary, Sahir; Lim, Caeul; Barnes, Samantha; Kocken, Clemens H M; Duraisingh, Manoj T; Adams, John H; Pasini, Erica M

    2016-07-01

    Malaria is one of the most significant tropical diseases, and of the Plasmodium species that cause human malaria, P. vivax is the most geographically widespread. However, P. vivax remains a relatively neglected human parasite since research is typically limited to laboratories with direct access to parasite isolates from endemic field settings or from non-human primate models. This restricted research capacity is in large part due to the lack of a continuous P. vivax in vitro culture system, which has hampered the ability for experimental research needed to gain biological knowledge and develop new therapies. Consequently, efforts to establish a long-term P. vivax culture system are confounded by our poor knowledge of the preferred host cell and essential nutrients needed for in vitro propagation. Reliance on very heterogeneous P. vivax field isolates makes it difficult to benchmark parasite characteristics and further complicates development of a robust and reliable culture method. In an effort to eliminate parasite variability as a complication, we used a well-defined Aotus-adapted P. vivax Sal-1 strain to empirically evaluate different short-term in vitro culture conditions and compare them with previous reported attempts at P. vivax in vitro culture Most importantly, we suggest that reticulocyte enrichment methods affect invasion efficiency and we identify stabilized forms of nutrients that appear beneficial for parasite growth, indicating that P. vivax may be extremely sensitive to waste products. Leuko-depletion methods did not significantly affect parasite development. Formatting changes such as shaking and static cultures did not seem to have a major impact while; in contrast, the starting haematocrit affected both parasite invasion and growth. These results support the continued use of Aotus-adapted Sal-1 for development of P. vivax laboratory methods; however, further experiments are needed to optimize culture conditions to support long-term parasite

  4. Insights into an Optimization of Plasmodium vivax Sal-1 In Vitro Culture: The Aotus Primate Model

    PubMed Central

    Obaldía, Nicanor; Nuñez, Marlon; Dutary, Sahir; Lim, Caeul; Barnes, Samantha; Kocken, Clemens H. M.; Duraisingh, Manoj T.; Adams, John H.; Pasini, Erica M.

    2016-01-01

    Malaria is one of the most significant tropical diseases, and of the Plasmodium species that cause human malaria, P. vivax is the most geographically widespread. However, P. vivax remains a relatively neglected human parasite since research is typically limited to laboratories with direct access to parasite isolates from endemic field settings or from non-human primate models. This restricted research capacity is in large part due to the lack of a continuous P. vivax in vitro culture system, which has hampered the ability for experimental research needed to gain biological knowledge and develop new therapies. Consequently, efforts to establish a long-term P. vivax culture system are confounded by our poor knowledge of the preferred host cell and essential nutrients needed for in vitro propagation. Reliance on very heterogeneous P. vivax field isolates makes it difficult to benchmark parasite characteristics and further complicates development of a robust and reliable culture method. In an effort to eliminate parasite variability as a complication, we used a well-defined Aotus-adapted P. vivax Sal-1 strain to empirically evaluate different short-term in vitro culture conditions and compare them with previous reported attempts at P. vivax in vitro culture Most importantly, we suggest that reticulocyte enrichment methods affect invasion efficiency and we identify stabilized forms of nutrients that appear beneficial for parasite growth, indicating that P. vivax may be extremely sensitive to waste products. Leuko-depletion methods did not significantly affect parasite development. Formatting changes such as shaking and static cultures did not seem to have a major impact while; in contrast, the starting haematocrit affected both parasite invasion and growth. These results support the continued use of Aotus-adapted Sal-1 for development of P. vivax laboratory methods; however, further experiments are needed to optimize culture conditions to support long-term parasite

  5. [Experimental whooping cough of nonhuman primate].

    PubMed

    Kubrava, D T; Medkova, A Iu; Siniashina, L N; Shevtsova, Z V; Matua, A Z; Kondzharia, I G; Barkaia, V S; Elistratova, Zh V; Karataev, G I; Mikvabia, Z Ia; Gintsburg, A L

    2013-01-01

    Despite considerable success in study of Bordetella pertussis virulence factors, pathogenesis of whooping cough, duration of B. pertussis bacteria persistence, types and mechanisms of immune response are still keep underinvestigated. It can be explained by the absence ofadequate experimental animal model for pertussis study. Our study estimates clinical and laboratory parameters of whooping cough in non-human primates of the Old World in the process of intranasan infection by virulent B. pertussis bacteria. Also the duration of B. pertussis bacteria persistence in animals was investigated. 14 animal units of 4 species of non-human primates of the Old World were used for intranasal infection. The examination of infect animals included: visual exploration of nasopharynx, thermometry, clinical and biochemical blood analyses, identification ofB. pertussis, using microbiologic and molecular genetic analyses, estimation of innate and adoptive immune factors. The development of infectious process was accompanied by generation of B. pertussis bacteria, catarrhal inflammation of nasopharyngeal mucosa, leucocytosis, hypoglycemia specific for pertussis, and activation of innate and adaptive immunity for all primates regardless of specie were seen. While repeated experimental infection in primates single bacterial colonies were registered during only first week after challenge. It occurs like the absence of inflammation of nasopharyngeal mucosa and the lack of laboratory marks of whooping cough, recorded after first challenge. The evident booster effect of humoral immunity was observed. As a model for investigation of B. pertussis bacteria persistence and immune response against whooping cough we suggest the usage of rhesus macaque as more available to experiments.

  6. The ecology of primate material culture

    PubMed Central

    Koops, Kathelijne; Visalberghi, Elisabetta; van Schaik, Carel P.

    2014-01-01

    Tool use in extant primates may inform our understanding of the conditions that favoured the expansion of hominin technology and material culture. The ‘method of exclusion’ has, arguably, confirmed the presence of culture in wild animal populations by excluding ecological and genetic explanations for geographical variation in behaviour. However, this method neglects ecological influences on culture, which, ironically, may be critical for understanding technology and thus material culture. We review all the current evidence for the role of ecology in shaping material culture in three habitual tool-using non-human primates: chimpanzees, orangutans and capuchin monkeys. We show that environmental opportunity, rather than necessity, is the main driver. We argue that a better understanding of primate technology requires explicit investigation of the role of ecological conditions. We propose a model in which three sets of factors, namely environment, sociality and cognition, influence invention, transmission and retention of material culture. PMID:25392310

  7. The ecology of primate material culture.

    PubMed

    Koops, Kathelijne; Visalberghi, Elisabetta; van Schaik, Carel P

    2014-11-01

    Tool use in extant primates may inform our understanding of the conditions that favoured the expansion of hominin technology and material culture. The 'method of exclusion' has, arguably, confirmed the presence of culture in wild animal populations by excluding ecological and genetic explanations for geographical variation in behaviour. However, this method neglects ecological influences on culture, which, ironically, may be critical for understanding technology and thus material culture. We review all the current evidence for the role of ecology in shaping material culture in three habitual tool-using non-human primates: chimpanzees, orangutans and capuchin monkeys. We show that environmental opportunity, rather than necessity, is the main driver. We argue that a better understanding of primate technology requires explicit investigation of the role of ecological conditions. We propose a model in which three sets of factors, namely environment, sociality and cognition, influence invention, transmission and retention of material culture.

  8. Stereotypic Behavior in Nonhuman Primates as a Model for the Human Condition

    PubMed Central

    Lutz, Corrine K.

    2014-01-01

    Stereotypies that develop spontaneously in nonhuman primates can provide an effective model for repetitive stereotyped behavior in people with neurodevelopmental or obsessive-compulsive disorders. The behaviors are similar in form, are similarly affected by environmental conditions, and are improved with similar treatment methods such as enrichment, training, and drug therapy. However, because of a greater number of commonalities in these factors, nonhuman primates may serve as a better model for stereotyped behavior in individuals with autism or intellectual disability than for compulsions in individuals with obsessive-compulsive disorder. Because animal models may not be exact in all features of the disorder being studied, it is important to investigate the strengths and weaknesses of using a nonhuman primate model for stereotyped behavior in people with psychological disorders. PMID:25225307

  9. TLR9 adjuvants enhance immunogenicity and protective efficacy of the SE36/AHG malaria vaccine in nonhuman primate models

    PubMed Central

    Tougan, Takahiro; Aoshi, Taiki; Coban, Cevayir; Katakai, Yuko; Kai, Chieko; Yasutomi, Yasuhiro; Ishii, Ken J.; Horii, Toshihiro

    2013-01-01

    The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Ongoing clinical trials suggest the efficacy of the SE36 vaccine could be increased by the incorporation of more effective adjuvants into the vaccine formulation. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. Administration of a crude extract of P. falciparum parasite resulted in the induction of more SE36-specific IgG antibodies in monkeys vaccinated with a combination of SE36/AHG and adjuvant, as opposed to vaccination with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized with the combined SE36/AHG and K3 ODN formulation effectively suppressed parasitemia and symptoms of malaria following challenge infections. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG demonstrates safety, potent immunogenicity and efficacy in nonhuman primates, and this vaccine formulation may form the basis of a more effective malaria vaccine. PMID:23291928

  10. Nonhuman Primate Model for Listeria monocytogenes-Induced Stillbirths

    PubMed Central

    Smith, Mary Alice; Takeuchi, Kazue; Brackett, Robert E.; McClure, Harold M.; Raybourne, Richard B.; Williams, Kristina M.; Babu, Uma S.; Ware, Glenn O.; Broderson, J. Roger; Doyle, Michael P.

    2003-01-01

    Listeria monocytogenes, isolated from outbreaks in either human or nonhuman primate populations, was administered orally at doses ranging from 106 to 1010 CFU. Four of 10 treated animals delivered stillborn infants. L. monocytogenes was isolated from fetal tissue, and the pathology was consistent with L. monocytogenes infection as the cause of pregnancy loss. For all pregnancies resulting in stillbirths, L. monocytogenes was isolated from maternal feces, indicating that L. monocytogenes had survived and had probably colonized the gastrointestinal tract. Antibodies and antigen-specific lymphocyte proliferation against Listeria increased in animals that had stillbirths. PMID:12595480

  11. Nonhuman primate models of addiction and PET imaging: dopamine system dysregulation.

    PubMed

    Gould, Robert W; Porrino, Linda J; Nader, Michael A

    2012-01-01

    This chapter highlights the use of nonhuman primate models of cocaine addiction and the use of positron emission tomography (PET) imaging to study the role of individual differences in vulnerability and how environmental and pharmacological variables can impact cocaine abuse. The chapter will describe studies related to the dopamine (DA) neurotransmitter system, and focus primarily on the D2-like DA receptor, the DA transporter and the use of fluorodeoxyglucose to better understand the neuropharmacology of cocaine abuse. The use of nonhuman primates allows for within-subject, longitudinal studies that have provided insight into the human condition and serve as an ideal model of translational research. The combination of nonhuman primate behavior, pharmacology and state-of-the-art brain imaging using PET will provide the foundation for future studies aimed at developing behavioral and pharmacological treatments for drug addiction in humans.

  12. Nonhuman Primate Models of Addiction and PET Imaging: Dopamine System Dysregulation

    PubMed Central

    Gould, Robert W.; Porrino, Linda J.; Nader, Michael A.

    2013-01-01

    This chapter highlights the use of nonhuman primate models of cocaine addiction and the use of positron emission tomography (PET) imaging to study the role of individual differences in vulnerability and how environmental and pharmacological variables can impact cocaine abuse. The chapter will describe studies related to the dopamine (DA) neurotransmitter system, and focus primarily on the D2-like DA receptor, the DA transporter and the use of fluorodeoxyglucose to better understand the neuropharmacology of cocaine abuse. The use of nonhuman primates allows for within-subject, longitudinal studies that have provided insight into the human condition and serve as an ideal model of translational research. The combination of nonhuman primate behavior, pharmacology and state-of-the-art brain imaging using PET will provide the foundation for future studies aimed at developing behavioral and pharmacological treatments for drug addiction in humans. PMID:22020537

  13. Large animal and primate models of spinal cord injury for the testing of novel therapies.

    PubMed

    Kwon, Brian K; Streijger, Femke; Hill, Caitlin E; Anderson, Aileen J; Bacon, Mark; Beattie, Michael S; Blesch, Armin; Bradbury, Elizabeth J; Brown, Arthur; Bresnahan, Jacqueline C; Case, Casey C; Colburn, Raymond W; David, Samuel; Fawcett, James W; Ferguson, Adam R; Fischer, Itzhak; Floyd, Candace L; Gensel, John C; Houle, John D; Jakeman, Lyn B; Jeffery, Nick D; Jones, Linda Ann Truett; Kleitman, Naomi; Kocsis, Jeffery; Lu, Paul; Magnuson, David S K; Marsala, Martin; Moore, Simon W; Mothe, Andrea J; Oudega, Martin; Plant, Giles W; Rabchevsky, Alexander Sasha; Schwab, Jan M; Silver, Jerry; Steward, Oswald; Xu, Xiao-Ming; Guest, James D; Tetzlaff, Wolfram

    2015-07-01

    Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose unique research questions prior to clinical trials, the role that such large animal and primate models should play in the translational pipeline is unclear. In this initiative we engaged members of the SCI research community in a questionnaire and round-table focus group discussion around the use of such models. Forty-one SCI researchers from academia, industry, and granting agencies were asked to complete a questionnaire about their opinion regarding the use of large animal and primate models in the context of testing novel therapeutics. The questions centered around how large animal and primate models of SCI would be best utilized in the spectrum of preclinical testing, and how much testing in rodent models was warranted before employing these models. Further questions were posed at a focus group meeting attended by the respondents. The group generally felt that large animal and primate models of SCI serve a potentially useful role in the translational pipeline for novel therapies, and that the rational use of these models would depend on the type of therapy and specific research question being addressed. While testing within these models should not be mandatory, the detection of beneficial effects using these models lends additional support for translating a therapy to humans. These models provides an opportunity to evaluate and refine surgical procedures prior to use in humans, and safety and bio-distribution in a spinal cord more similar in size and anatomy to that of humans. Our results reveal that while many feel that these models are valuable in the testing of novel therapies, important questions remain unanswered about how they should be used and how data derived from them should be interpreted.

  14. [Squirrel monkey--an ideal primate (correction of prmate) model of space physiology].

    PubMed

    Matsunami, K

    1997-06-01

    Investigation of the vestibulo-ocular system of the squirrel monkey was reviewed in consideration of space motion sickness (SMS), or which is recently more often termed as space adaptation syndrome (SAS). Since the first launching of the space satellite, Sputnik [correction of Sputonik] in October 1957, many experiments were carried out in biological and medical fields. A various kind of creatures were used as experimental models from protozoa to human beings. Rats and monkeys are most favorite animals, particularly the non-human primate seems to be the one, because of its phylogenetic relatives akin to the human beings. Chimpanzees, rhesus monkeys, pig tailed-monkeys, red-faced monkeys and squirrel monkeys have been used mostly in American space experiments. Russian used rhesus monkeys. Among these, however, the squirrel monkey has an advantage of the small size of the body, ranging from 600- l000g in adult. This small size as a primate is very advantageous in experiments conducted in a narrow room of the space satellite or shuttle because of its space-saving. The squirrel monkey has another advantage to rear easily as is demonstrated to keep it as a pet. Accordingly, this petit animal provides us a good animal model in biological and medical experiments in space craft. The size of the brain of the squirrel monkey is extraordinary large relative to the body size, which is even superior to that of the human beings. This is partly owed to enlargement of the occipito-temporal cortices, which are forced to well develop for processing a huge amount of audio-visual information indispensable to the arboreal habitant to survive in tropical forest. The vestibular system of the squirrel monkey seems to be the most superior as well, when judged from it relative size of the vestibular nuclear complex. Balancing on swinging twigs or jumping from tree to tree developed the capability of this equilibrium system. Fernandez, Goldberg and his collaborators used the squirrel monkey

  15. Operant conditioning of a multiple degree-of-freedom brain-machine interface in a primate model of amputation.

    PubMed

    Balasubramanian, Karthikeyan; Southerland, Joshua; Vaidya, Mukta; Qian, Kai; Eleryan, Ahmed; Fagg, Andrew H; Sluzky, Marc; Oweiss, Karim; Hatsopoulos, Nicholas

    2013-01-01

    Operant conditioning with biofeedback has been shown to be an effective method to modify neural activity to generate goal-directed actions in a brain-machine interface. It is particularly useful when neural activity cannot be mathematically mapped to motor actions of the actual body such as in the case of amputation. Here, we implement an operant conditioning approach with visual feedback in which an amputated monkey is trained to control a multiple degree-of-freedom robot to perform a reach-to-grasp behavior. A key innovation is that each controlled dimension represents a behaviorally relevant synergy among a set of joint degrees-of-freedom. We present a number of behavioral metrics by which to assess improvements in BMI control with exposure to the system. The use of non-human primates with chronic amputation is arguably the most clinically-relevant model of human amputation that could have direct implications for developing a neural prosthesis to treat humans with missing upper limbs.

  16. Between the primate and ‘reptilian’ brain: rodent models demonstrate the role of corticostriatal circuits in decision making

    PubMed Central

    Zador, Anthony; Wilbrecht, Linda

    2015-01-01

    Decision making can be defined as the flexible integration and transformation of information from the external world into action. Recently, the development of novel genetic tools and new behavioral paradigms has made it attractive to study behavior of all kinds in rodents. By some perspectives, rodents are not an acceptable model for the study of decision making due to their simpler behavior often attributed to their less extensive cortical development when compared to non-human primates. We argue that decision making can be approached with a common framework across species. We review insights from comparative anatomy that suggest the expansion of cortical-striatal connectivity is a key development in evolutionary increases in behavioral flexibility. We briefly review studies that establish a role for corticostriatal circuits in integrative decision making. Finally, we provide an overview of a few recent, highly complementary rodent decision making studies using genetic tools, revealing with new cellular and temporal resolution how, when and where information can be integrated and compared in striatal circuits to influence choice. PMID:25575943

  17. A new conservation strategy for China-A model starting with primates.

    PubMed

    Pan, Ruliang; Oxnard, Charles; Grueter, Cyril C; Li, Baoguo; Qi, Xiaoguang; He, Gang; Guo, Songtao; Garber, Paul A

    2016-11-01

    Although the evolutionary history of primates in China dates to the Eocene, and includes major radiations of lorisids, hominoids, cercopithecines, and colobines during the Miocene, Pliocene, and Pleistocene, extensive human-induced habitat change and deforestation over the past few centuries has resulted in 22 of 25 extant species listed as threatened or endangered, and two species of gibbons extirpated in the last few years. This commentary briefly reviews factors that have contributed to the decline of primates in China over the past 400 years, and in particular how major social events and economic development in modern China have resulted in unsustainable environmental change. In response, we describe our efforts to develop a strategic scientific, educational and conservation partnership in China, focusing on primates, in which GIS technology will be used to integrate geographical profiles, climatic information, and changes in land use patterns and human and nonhuman primate distributions to highlight issues of immediate concern and to develop priority-based conservation solutions. Our goal is to evaluate how human-induced environmental change has impacted primates over time and to predict the likelihood of primate population extinctions in the near future. This model represents an early warning system that will be widely available to the Chinese government, public, educational institutions, researchers, and NGOs through social media and educational videos in order to arouse public awareness and promote wildlife conservation. We encourage colleagues across a broad range of academic disciplines, political ideologies, and the public to help move this strategy into reality, the sooner the better. Am. J. Primatol. 78:1137-1148, 2016. © 2016 Wiley Periodicals, Inc.

  18. Toward a nonhuman primate model of fetal programming: phenotypic plasticity of the common marmoset fetoplacental complex.

    PubMed

    Rutherford, Julienne N

    2012-11-01

    Nonhuman primates offer unique opportunities as animal models in the study of developmental programming and the role of the placenta in developmental processes. All primates share fundamental similarities in life history and reproductive biology. Thus, insights gleaned from studies of nonhuman primates have a higher degree of biological salience to human biology than do studies of rodents or agricultural animals. The common marmoset monkey is a small-bodied primate from South America that produces litters of dizygotic fetuses that share a single placental mass. This natural variation allows us to model different intrauterine conditions and associated fetoplacental phenotypes. The marmoset placenta is phenotypically plastic according to litter size. Triplet litters are characterized by low individual fetal weights and significantly more efficient placentas and attendant alterations to the microscopic architecture and endocrine function, thus modeling a nutrient restricted intrauterine environment. Consistent with this model, triplet neonates experience a higher risk of perinatal mortality and an increased likelihood of elevated adult weight. Recent evidence has shown that the intrauterine experience of females has an impact on their own pregnancy outcomes in adulthood: triplet females experience significantly greater pregnancy loss than do twin females. The marmoset monkey thus represents a potential powerful nonhuman primate model of multiple pregnancies, restrictive prenatal experiences, and differential reproductive outcomes in adulthood, which may have important implications for studying the impact of in vitro fertilization on adult reproductive health. It is still too early to determine exactly what developmental pathways lead to this disparity or what specific role the placenta plays; future work on this front will be critical to establish the marmoset as an important model of fetal programming of reproductive function in adulthood and across generations.

  19. Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models.

    PubMed

    Guan, Xin; Qin, Meng; Zhang, Yu; Wang, Yanan; Shen, Bin; Ren, Zhihua; Ding, Xinxin; Dai, Wei; Jiang, Yongping

    2017-03-01

    Because of a lack of platelet supply and a U.S. Food and Drug Administration-approved platelet growth factor, megakaryocytes have emerged as an effective substitute for alleviating thrombocytopenia. Here, we report the development of an efficient two-stage culture system that is free of stroma, animal components, and genetic manipulations for the production of functional megakaryocytes from hematopoietic stem cells. Safety and functional studies were performed in murine and nonhuman primate models. One human cryopreserved cord blood CD34(+) cell could be induced ex vivo to produce up to 1.0 × 10(4) megakaryocytes that included CD41a(+) and CD42b(+) cells at 82.4% ± 6.1% and 73.3% ± 8.5% (mean ± SD), respectively, yielding approximately 650-fold higher cell numbers than reported previously. Induced human megakaryocytic cells were capable of engrafting and producing functional platelets in the murine xenotransplantation model. In the nonhuman primate model, transplantation of primate megakaryocytic progenitors increased platelet count nadir and enhanced hemostatic function with no adverse effects. In addition, primate platelets were released in vivo as early as 3 hours after transplantation with autologous or allogeneic mature megakaryocytes and lasted for more than 48 hours. These results strongly suggest that large-scale induction of functional megakaryocytic cells is applicable for treating thrombocytopenic blood diseases in the clinic. Stem Cells Translational Medicine 2017;6:897-909.

  20. Body size and the small branch niche: using marsupial ontogeny to model primate locomotor evolution.

    PubMed

    Shapiro, Liza J; Young, Jesse W; VandeBerg, John L

    2014-03-01

    Recently proposed ancestral locomotor and morphological 'stages' leading to the evolution of primates have emphasized small body size, and a transition from a clawed non-grasping stage, to a clawed, grasping stage with clawless opposable hallux, to a fully-nailed primate with grasping extremities. This evolutionary transition was presumably associated with frequent use of the small branch niche. To model elements of these evolutionary transitions, we investigate how body size, substrate size, substrate orientation and grasping morphology interact to influence quadrupedal kinematics within and between ontogenetic samples of two small-bodied marsupials, one arboreal (Petaurus breviceps) and the other mainly terrestrial (Monodelphis domestica). Longitudinal morphometric and kinematic data were collected from four juvenile P. breviceps (33-75 g) and two juvenile M. domestica (18-95 g) walking across poles of three diameters (2.5, 1.0, and 0.5 cm) and three orientations (horizontal, 30° incline, 30° decline). The two species responded similarly to some substrate conditions, but diverged in response to others. Kinematic divergence between the two species reflects Monodelphis' relatively shorter digits, reduced grasping ability and greater need for stabilizing mechanisms on narrow substrates. At a given relative body size or pole orientation, Monodelphis used higher limb duty factors, more limbs in support per stride, lower limb phases, and in some conditions, faster speeds compared with Petaurus. Interspecific differences were the least distinct on declined poles, highlighting the particular challenge of this substrate condition, even for arboreally adapted species. Small-bodied, arboreal primate ancestors would likely have employed the kinematic mechanisms common to our model taxa, but those with enhanced grasping adaptations would most likely not have required the increased level of stabilizing mechanisms exhibited by Monodelphis. Thus, using these two species

  1. Refining reproductive parameters for modelling sustainability and extinction in hunted primate populations in the Amazon.

    PubMed

    Bowler, Mark; Anderson, Matt; Montes, Daniel; Pérez, Pedro; Mayor, Pedro

    2014-01-01

    Primates are frequently hunted in Amazonia. Assessing the sustainability of hunting is essential to conservation planning. The most-used sustainability model, the 'Production Model', and more recent spatial models, rely on basic reproductive parameters for accuracy. These parameters are often crudely estimated. To date, parameters used for the Amazon's most-hunted primate, the woolly monkey (Lagothrix spp.), come from captive populations in the 1960s, when captive births were rare. Furthermore, woolly monkeys have since been split into five species. We provide reproductive parameters calculated by examining the reproductive organs of female Poeppig's woolly monkeys (Lagothrix poeppigii), collected by hunters as part of their normal subsistence activity. Production was 0.48-0.54 young per female per year, and an interbirth interval of 22.3 to 25.2 months, similar to parameters from captive populations. However, breeding was seasonal, which imposes limits on the maximum reproductive rate attainable. We recommend the use of spatial models over the Production Model, since they are less sensitive to error in estimated reproductive rates. Further refinements to reproductive parameters are needed for most primate taxa. Methods like ours verify the suitability of captive reproductive rates for sustainability analysis and population modelling for populations under differing conditions of hunting pressure and seasonality. Without such research, population modelling is based largely on guesswork.

  2. Refining Reproductive Parameters for Modelling Sustainability and Extinction in Hunted Primate Populations in the Amazon

    PubMed Central

    Bowler, Mark; Anderson, Matt; Montes, Daniel; Pérez, Pedro; Mayor, Pedro

    2014-01-01

    Primates are frequently hunted in Amazonia. Assessing the sustainability of hunting is essential to conservation planning. The most-used sustainability model, the ‘Production Model’, and more recent spatial models, rely on basic reproductive parameters for accuracy. These parameters are often crudely estimated. To date, parameters used for the Amazon’s most-hunted primate, the woolly monkey (Lagothrix spp.), come from captive populations in the 1960s, when captive births were rare. Furthermore, woolly monkeys have since been split into five species. We provide reproductive parameters calculated by examining the reproductive organs of female Poeppig’s woolly monkeys (Lagothrix poeppigii), collected by hunters as part of their normal subsistence activity. Production was 0.48–0.54 young per female per year, and an interbirth interval of 22.3 to 25.2 months, similar to parameters from captive populations. However, breeding was seasonal, which imposes limits on the maximum reproductive rate attainable. We recommend the use of spatial models over the Production Model, since they are less sensitive to error in estimated reproductive rates. Further refinements to reproductive parameters are needed for most primate taxa. Methods like ours verify the suitability of captive reproductive rates for sustainability analysis and population modelling for populations under differing conditions of hunting pressure and seasonality. Without such research, population modelling is based largely on guesswork. PMID:24714614

  3. Effects of antithrombotic agents evaluated in a nonhuman primate vascular shunt model.

    PubMed Central

    Mason, R. G.; Wolf, R. H.; Zucker, W. H.; Shinoda, B. A.; Mohammad, S. F.

    1976-01-01

    The effects of aspirin, cyproheptadine, dextran, dipyridamole, and sulfinpyrazone on thrombus deposition were determined. These antithrombotic agents were evaluated in a nonhuman primate model for thrombus generation that employed test devices exposed to blood in an arteriovenous shunt. Thrombus deposition on test devices was quantitated gravimetrically. Of the antithrombotic agents tested, cyproheptadine was found to be the most effective, and aspirin, dextran, and dipyridamole were each somewhat less effective. Sulfinpyrazone had only a slight antithrombotic effect. Ultrastructual studies of thrombus deposited in test devices showed that the various antithrombotic agents tested did not prevent completely the formation of fibrin, aggregation of platelets, or adhesion and spreading of platelets and leukocytes. This model for thrombus generation is felt to be a more efficient means for evaluating antithrombotic agents than previously described nonhuman primate models. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:820202

  4. Connections Matter: Social Networks and Lifespan Health in Primate Translational Models

    PubMed Central

    McCowan, Brenda; Beisner, Brianne; Bliss-Moreau, Eliza; Vandeleest, Jessica; Jin, Jian; Hannibal, Darcy; Hsieh, Fushing

    2016-01-01

    Humans live in societies full of rich and complex relationships that influence health. The ability to improve human health requires a detailed understanding of the complex interplay of biological systems that contribute to disease processes, including the mechanisms underlying the influence of social contexts on these biological systems. A longitudinal computational systems science approach provides methods uniquely suited to elucidate the mechanisms by which social systems influence health and well-being by investigating how they modulate the interplay among biological systems across the lifespan. In the present report, we argue that nonhuman primate social systems are sufficiently complex to serve as model systems allowing for the development and refinement of both analytical and theoretical frameworks linking social life to health. Ultimately, developing systems science frameworks in nonhuman primate models will speed discovery of the mechanisms that subserve the relationship between social life and human health. PMID:27148103

  5. Antinociceptive effect of clinical analgesics in a nonhuman primate model of knee osteoarthritis.

    PubMed

    Ogawa, Shinya; Awaga, Yuji; Takashima, Miyuki; Hama, Aldric; Matsuda, Akihisa; Takamatsu, Hiroyuki

    2016-09-05

    A number of potential analgesic pharmacotherapies developed in preclinical osteoarthritis animal models have failed clinical trials. A possible basis for the lack of translation of preclinical findings to clinical efficacy is the use of a preclinical species that is distinct from that of humans. The current study tested clinical analgesics in a nonhuman primate model of knee osteoarthritis. Following a medial meniscectomy, the animals developed a robust ipsilateral reduction in knee pressure threshold (hyperalgesia) and an ipsilateral reduction in weight bearing (resting pain). The serotonin-noradrenalin reuptake inhibitor duloxetine and opioid morphine increased ipsilateral pressure threshold and weight bearing. By contrast, the anticonvulsant pregabalin did not affect either pressure hyperalgesia or resting pain. The current findings in the nonhuman primate model of osteoarthritis parallel clinical findings, in that duloxetine and opioids are used in the management of osteoarthritis pain whereas pregabalin is not. The current findings also suggest the possible differentiation of pharmacotherapeutics in a nonhuman primate model, of distinguishing potential clinically useful analgesics for the management of osteoarthritic pain from those that are not.

  6. Early blood plutonium retention in nonhuman primates compared to the NCRP 156 wound biokinetic model.

    PubMed

    Konzen, Kevin; Brey, Richard; Guilmette, Raymond

    2015-03-01

    Data from animal experiments are relied upon for understanding the biokinetics of contaminant retention and excretion where insufficient human data exist. Records involving nonhuman primate experiments performed from 1973 to 1987 were collected and compiled by researchers at the Lawrence Berkeley Laboratory. These records included early blood samples that were taken after soluble plutonium was administered via intramuscular, subcutaneous, or intravenous injection. Samples were collected as early as 5 min post injection with several samples collected during the first few weeks. The NCRP 156 biokinetic model was developed primarily from animal experiments due to insufficient human data not influenced by chelation therapy. This work compared the NCRP 156 biokinetic model default transfer rate constants to the early blood excretion data from nonhuman primate experiments for 238Pu. These results indicated that the blood content of nonhuman primates exhibited "moderate" retention properties for simulated wound conditions. Additionally, there was no evidence of long-term retention of plutonium in the whole blood samples, confirming that plutonium was not incorporated within blood cells. Particle solubility characteristics should be considered for wounds when using the NCRP 156 wound biokinetic model.

  7. The brain's router: a cortical network model of serial processing in the primate brain.

    PubMed

    Zylberberg, Ariel; Fernández Slezak, Diego; Roelfsema, Pieter R; Dehaene, Stanislas; Sigman, Mariano

    2010-04-29

    The human brain efficiently solves certain operations such as object recognition and categorization through a massively parallel network of dedicated processors. However, human cognition also relies on the ability to perform an arbitrarily large set of tasks by flexibly recombining different processors into a novel chain. This flexibility comes at the cost of a severe slowing down and a seriality of operations (100-500 ms per step). A limit on parallel processing is demonstrated in experimental setups such as the psychological refractory period (PRP) and the attentional blink (AB) in which the processing of an element either significantly delays (PRP) or impedes conscious access (AB) of a second, rapidly presented element. Here we present a spiking-neuron implementation of a cognitive architecture where a large number of local parallel processors assemble together to produce goal-driven behavior. The precise mapping of incoming sensory stimuli onto motor representations relies on a "router" network capable of flexibly interconnecting processors and rapidly changing its configuration from one task to another. Simulations show that, when presented with dual-task stimuli, the network exhibits parallel processing at peripheral sensory levels, a memory buffer capable of keeping the result of sensory processing on hold, and a slow serial performance at the router stage, resulting in a performance bottleneck. The network captures the detailed dynamics of human behavior during dual-task-performance, including both mean RTs and RT distributions, and establishes concrete predictions on neuronal dynamics during dual-task experiments in humans and non-human primates.

  8. Direct comparison of cognitive facilitation by physostigmine and tetrahydroaminoacridine in two primate models.

    PubMed

    Rupniak, N M; Field, M J; Samson, N A; Steventon, M J; Iversen, S D

    1990-01-01

    Cognitive facilitation by physostigmine and tetrahydroaminoacridine (THA) was compared in two primate models. Disruption of spatial delayed response performance by scopolamine (0.03 mg/kg) was fully reversed by coadministration of 5 doses of physostigmine in the range 0.03-0.08 mg/kg, but by only one dose (4.0 mg/kg) of THA; partial reversal of some effects of scopolamine was observed at 1 and 3 mg/kg of THA. Visual recognition memory was enhanced following treatment with 4 doses of physostigmine in the range 0.001-0.03 mg/kg. The effect of THA across the group of animals was not significant but performance tended to improve using a dose of 0.8 mg/kg. Our findings indicate that THA does not have a superior profile to physostigmine as a cognitive enhancer in primates.

  9. Thermal modeling of millimeter wave damage to the primate cornea at 35 GHz and 94 GHz.

    PubMed

    Foster, Kenneth R; D'Andrea, John A; Chalfin, Steven; Hatcher, Donald J

    2003-06-01

    Recent data on damage to the primate cornea from exposure to millimeter wave radiation are interpreted in terms of a simple thermal model. The measured temperature increases during the exposures (duration 1-5 s, 35 or 94 GHz, 2-7 W cm(-2)) agree with the model within the variability of the data. The thresholds for damage to the cornea (staining of the corneal epithelium by fluorescein and corneal edema) correspond to temperature increases of about 20 degrees C at both irradiation frequencies. Within the limits of the one-dimensional model, thresholds for thermal damage to the cornea can be predicted for a range of exposure conditions.

  10. Linear-Nonlinear-Poisson Models of Primate Choice Dynamics

    PubMed Central

    Corrado, Greg S; Sugrue, Leo P; Sebastian Seung, H; Newsome, William T

    2005-01-01

    The equilibrium phenomenon of matching behavior traditionally has been studied in stationary environments. Here we attempt to uncover the local mechanism of choice that gives rise to matching by studying behavior in a highly dynamic foraging environment. In our experiments, 2 rhesus monkeys (Macacca mulatta) foraged for juice rewards by making eye movements to one of two colored icons presented on a computer monitor, each rewarded on dynamic variable-interval schedules. Using a generalization of Wiener kernel analysis, we recover a compact mechanistic description of the impact of past reward on future choice in the form of a Linear-Nonlinear-Poisson model. We validate this model through rigorous predictive and generative testing. Compared to our earlier work with this same data set, this model proves to be a better description of choice behavior and is more tightly correlated with putative neural value signals. Refinements over previous models include hyperbolic (as opposed to exponential) temporal discounting of past rewards, and differential (as opposed to fractional) comparisons of option value. Through numerical simulation we find that within this class of strategies, the model parameters employed by animals are very close to those that maximize reward harvesting efficiency. PMID:16596981

  11. In vivo biological effects of stereotactic radiosurgery: A primate model

    SciTech Connect

    Lunsford, L.D.; Altschuler, E.M.; Flickinger, J.C.; Wu, A.; Martinez, A.J. )

    1990-09-01

    Single-fraction, closed skull, small-volume irradiation (radiosurgery) of intact intracranial structures requires accurate knowledge of radiation tolerance. We have developed a baboon model to assess the in vivo destructive radiobiological effects of stereotactic radiosurgery. Three baboons received a single-fraction, 150-Gy lesion of the caudate nucleus, the thalamus, or the pons using the 8-mm diameter collimator of the gamma unit. Serial standard neurodiagnostic tests (neurological examination, computed tomographic scan, magnetic resonance imaging, stable xenon-enhanced computed tomographic scan of cerebral blood flow, somatosensory and brain stem evoked potentials, and myelin basic protein levels of cerebrospinal fluid) were compared with preoperative studies. Magnetic resonance imaging revealed the development of a lesion at the target site between 45 and 60 days after irradiation. Deterioration of the brain stem evoked potentials preceded imaging changes when the lesion encroached on auditory pathways. Myelin basic protein levels increased subsequent to imaging changes. Postmortem neuropathological examination confirmed a well-demarcated radionecrosis of the target volume. The baboon model appears to be an excellent method to study the in vivo biological effects of radiosurgery.

  12. A Review of the Comparative Anatomy, Histology, Physiology and Pathology of the Nasal Cavity of Rats, Mice, Dogs and Non-human Primates. Relevance to Inhalation Toxicology and Human Health Risk Assessment.

    PubMed

    Chamanza, R; Wright, J A

    2015-11-01

    There are many significant differences in the structural and functional anatomy of the nasal cavity of man and laboratory animals. Some of the differences may be responsible for the species-specific nasal lesions that are often observed in response to inhaled toxicants. This paper reviews the comparative anatomy, physiology and pathology of the nasal cavity of the rat, mouse, dog, monkey and man, highlighting factors that may influence the distribution of nasal lesions. Gross anatomical variations such as turbinate structure, folds or grooves on nasal walls, or presence or absence of accessory structures, may influence nasal airflow and species-specific uptake and deposition of inhaled material. In addition, interspecies variations in the morphological and biochemical composition and distribution of the nasal epithelium may affect the local tissue susceptibility and play a role in the development of species-specific nasal lesions. It is concluded that, while the nasal cavity of the monkey might be more similar to that of man, each laboratory animal species provides a model that responds in a characteristic and species-specific manner. Therefore for human risk assessment, careful consideration must be given to the anatomical differences between a given animal model and man.

  13. Life history of the most complete fossil primate skeleton: exploring growth models for Darwinius

    PubMed Central

    López-Torres, Sergi; Schillaci, Michael A.; Silcox, Mary T.

    2015-01-01

    Darwinius is an adapoid primate from the Eocene of Germany, and its only known specimen represents the most complete fossil primate ever found. Its describers hypothesized a close relationship to Anthropoidea, and using a Saimiri model estimated its age at death. This study reconstructs the ancestral permanent dental eruption sequences for basal Euprimates, Haplorhini, Anthropoidea, and stem and crown Strepsirrhini. The results show that the ancestral sequences for the basal euprimate, haplorhine and stem strepsirrhine are identical, and similar to that of Darwinius. However, Darwinius differs from anthropoids by exhibiting early development of the lower third molars relative to the lower third and fourth premolars. The eruption of the lower second premolar marks the point of interruption of the sequence in Darwinius. The anthropoid Saimiri as a model is therefore problematic because it exhibits a delayed eruption of P2. Here, an alternative strepsirrhine model based on Eulemur and Varecia is presented. Our proposed model shows an older age at death than previously suggested (1.05–1.14 years), while the range for adult weight is entirely below the range proposed previously. This alternative model is more consistent with hypotheses supporting a stronger relationship between adapoids and strepsirrhines. PMID:26473056

  14. Models of stress in nonhuman primates and their relevance for human psychopathology and endocrine dysfunction.

    PubMed

    Meyer, Jerrold S; Hamel, Amanda F

    2014-01-01

    Stressful life events have been linked to the onset of severe psychopathology and endocrine dysfunction in many patients. Moreover, vulnerability to the later development of such disorders can be increased by stress or adversity during development (e.g., childhood neglect, abuse, or trauma). This review discusses the methodological features and results of various models of stress in nonhuman primates in the context of their potential relevance for human psychopathology and endocrine dysfunction, particularly mood disorders and dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Such models have typically examined the effects of stress on the animals' behavior, endocrine function (primarily the HPA and hypothalamic-pituitary-gonadal systems), and, in some cases, immune status. Manipulations such as relocation and/or removal of an animal from its current social group or, alternatively, formation of a new social group can have adverse effects on all of these outcome measures that may be either transient or more persistent depending on the species, sex, and other experimental conditions. Social primates may also experience significant stress associated with their rank in the group's dominance hierarchy. Finally, stress during prenatal development or during the early postnatal period may have long-lasting neurobiological and endocrine effects that manifest in an altered ability to cope behaviorally and physiologically with later challenges. Whereas early exposure to severe stress usually results in deficient coping abilities, certain kinds of milder stressors can promote subsequent resilience in the animal. We conclude that studies of stress in nonhuman primates can model many features of stress exposure in human populations and that such studies can play a valuable role in helping to elucidate the mechanisms underlying the role of stress in human psychopathology and endocrine dysfunction.

  15. Models of Stress in Nonhuman Primates and Their Relevance for Human Psychopathology and Endocrine Dysfunction

    PubMed Central

    Meyer, Jerrold S.; Hamel, Amanda F.

    2014-01-01

    Stressful life events have been linked to the onset of severe psychopathology and endocrine dysfunction in many patients. Moreover, vulnerability to the later development of such disorders can be increased by stress or adversity during development (e.g., childhood neglect, abuse, or trauma). This review discusses the methodological features and results of various models of stress in nonhuman primates in the context of their potential relevance for human psychopathology and endocrine dysfunction, particularly mood disorders and dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Such models have typically examined the effects of stress on the animals' behavior, endocrine function (primarily the HPA and hypothalamic-pituitary-gonadal systems), and, in some cases, immune status. Manipulations such as relocation and/or removal of an animal from its current social group or, alternatively, formation of a new social group can have adverse effects on all of these outcome measures that may be either transient or more persistent depending on the species, sex, and other experimental conditions. Social primates may also experience significant stress associated with their rank in the group's dominance hierarchy. Finally, stress during prenatal development or during the early postnatal period may have long-lasting neurobiological and endocrine effects that manifest in an altered ability to cope behaviorally and physiologically with later challenges. Whereas early exposure to severe stress usually results in deficient coping abilities, certain kinds of milder stressors can promote subsequent resilience in the animal. We conclude that studies of stress in nonhuman primates can model many features of stress exposure in human populations and that such studies can play a valuable role in helping to elucidate the mechanisms underlying the role of stress in human psychopathology and endocrine dysfunction. PMID:25225311

  16. The tree shrews: adjuncts and alternatives to primates as models for biomedical research.

    PubMed

    Cao, J; Yang, E-B; Su, J-J; Li, Y; Chow, P

    2003-06-01

    The tree shrews are non-rodent, primate-like, small animals. There is increasing interest in using them to establish animal models for medical and biological research. This review focuses on the use of the tree shrews in in vivo studies on viral hepatitis, hepatocellular carcinoma (HCC), myopia, and psychosocial stress. Because of the susceptibility of the tree shrews (Tupaia belangeri) and their hepatocytes to infection with human hepatitis B virus (HBV) in vivo and in vitro, these animals have been used to establish human hepatitis virus-induced hepatitis and human HBV- and aflatoxin B1-associated HCC models. As these animals are phylogenetically close to primates in evolution and have a well-developed visual system and color vision in some species, they have been utilized to establish myopia models. Because dramatic behavioral, physiological, and neuroendocrine changes in subordinate male tree shrews are similar to those observed in depressed human patients, the tree shrews have been successfully employed to experimentally study psychosocial stress. However, the tree shrews holds significant promise as research models and great use could be made of these animals in biomedical research.

  17. Visual categorization: accessing abstraction in non-human primates.

    PubMed Central

    Fabre-Thorpe, Michèle

    2003-01-01

    Evolution might have set the basic foundations for abstract mental representation long ago. Because of language, mental abilities would have reached different degrees of sophistication in mammals and in humans but would be, essentially, of the same nature. Thus, humans and animals might rely on the same basic mechanisms that could be masked in humans by the use of sophisticated strategies. In this paper, monkey and human abilities are compared in a variety of perceptual tasks including visual categorization to assess behavioural similarities and dissimilarities, and to determine the level of abstraction of monkeys' mental representations. The question of how these abstract representations might be encoded in the brain is then addressed. A comparative study of the neural processing underlying abstract cognitive operations in animals and humans might help to understand when abstraction emerged in the phylogenetic scale, and how it increased in complexity. PMID:12903657

  18. Non-human primates: a comparative developmental perspective on yawning.

    PubMed

    Anderson, James R

    2010-01-01

    There is a long history of yawning in Old World monkeys being viewed as a form of communication, in particular, as a kind of threat. Yawning in agonistic and tense situations is seen in adult males, in particular, and it varies with male hormonal levels and social status. Experiments are reviewed that demonstrate operant control of the rate of yawning in adult male macaques, using food rewards. This indicates a degree of flexibility in the production of yawning. However, although adult male Old World monkeys often engage in 'canine contests', there is little evidence for the contagious yawning seen in humans. Experiments are reviewed showing that chimpanzees tested under comparable conditions to human adults, namely exposed to video sequences showing yawns, may yawn contagiously to yawn stimuli. Chimpanzees also yawn to computer animations of yawns. There is controversy in the literature over whether other species, including dogs and some monkeys, may also show contagious yawning. Further research is required to address unresolved issues. A hypothesis is put forward that in modern industrial society adults' natural pattern of yawning is inhibited, and that being reminded to yawn by seeing another individual yawn (contagious yawning) can help us to catch up on missed yawns. This would explain the lack of contagious yawning reported in young children and chimpanzees in natural surroundings, as these populations do not have the same social constraints on yawning.

  19. Mast cell heterogeneity in non-human primates

    SciTech Connect

    Barrett, K.E.; Szucs, E.F.; Metcalfe, D.D.

    1986-03-05

    Mast cells of rodents may be subdivided in terms of their properties, but the extent of such heterogeneity in man and higher animals is still unknown. The authors have compared lung (LMC) and intestinal (IMC) mast cells obtained from individual monkeys. LMC contained more histamine (HA) than IMC (6.61+/-1.3 vs. 1.6+/-0.6 pg/cell, means+/-SEM, n=3). LMC released more HA (17.7+/-2.1% vs. 9.2+/-1.0%, means+/-SEM, n=16) and also generated more LTC/sub 4/ equivalents as measured by radioimmunoassay (range 13.4-41.5 vs. 3.0-4.0 ng/10/sup 6/ mast cells) following an anaphylactic stimulus. The majority (>90%) of LMC stained metachromatically under conditions appropriate for heparin-containing cells, whereas IMC required more forcing conditions to display metachromasia. In contrast to these quantitative and qualitative mediator differences, functional responses of LMC and IMC were similar. Thus, HA release was inhibited comparably by theophylline, isoprenaline and dibutyryl cyclic AMP, but quercetin was slightly more active on IMC. Substance P caused dose-related HA release from both cell types, although the amount released varied between individual animal, (range LMC 1.2-20.2%, IMC 1.8-23.0%, n=4). Other neuropeptides (pentagastrin) vasoactive intestinal peptide, neurotensin, somatostatin) did not release HA. They conclude that mast cell heterogeneity in higher animals may be reflected more by cytochemical rather than functional differences between mast cell classes.

  20. Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever.

    PubMed

    Marzi, Andrea; Yoshida, Reiko; Miyamoto, Hiroko; Ishijima, Mari; Suzuki, Yasuhiko; Higuchi, Megumi; Matsuyama, Yukie; Igarashi, Manabu; Nakayama, Eri; Kuroda, Makoto; Saijo, Masayuki; Feldmann, Friederike; Brining, Douglas; Feldmann, Heinz; Takada, Ayato

    2012-01-01

    Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.

  1. α-Synuclein and nonhuman primate models of Parkinson’s disease

    PubMed Central

    Vermilyea, Scott C.; Emborg, Marina E.

    2015-01-01

    Accumulation of α-synuclein (α-syn) leading to the formation of insoluble intracellular aggregates named Lewy bodies is proposed to have a significant role in Parkinson’s disease (PD) pathology. Nonhuman primate (NHP) models of PD have proven essential for understanding the neurobiological basis of the disease and for the preclinical evaluation of first-in-class and invasive therapies. In addition to neurotoxin, aging and intracerebral gene transfer models, a new generation of models using inoculations of α-syn formulations, as well as transgenic methods is emerging. Understanding of their advantages and limitations will be essential when choosing a platform to evaluate α-syn-related pathology and interpreting the test results of new treatments targeting α-syn aggregation. In this review we aim to provide insight on this issue by critically analyzing the differences in endogenous α-syn, as well as α-syn pathology in PD and PD NHP models. PMID:26247888

  2. Hydrogen and Oxygen Isotope Ratios in Body Water and Hair: Modeling Isotope Dynamics in Nonhuman Primates

    PubMed Central

    O’Grady, Shannon P.; Valenzuela, Luciano O.; Remien, Christopher H.; Enright, Lindsey E.; Jorgensen, Matthew J.; Kaplan, Jay R.; Wagner, Janice D.; Cerling, Thure E.; Ehleringer, James R.

    2012-01-01

    The stable isotopic composition of drinking water, diet, and atmospheric oxygen influence the isotopic composition of body water (2H/1H, 18O/16O expressed as δ2H and δ18O). In turn, body water influences the isotopic composition of organic matter in tissues, such as hair and teeth, which are often used to reconstruct historical dietary and movement patterns of animals and humans. Here, we used a nonhuman primate system (Macaca fascicularis) to test the robustness of two different mechanistic stable isotope models: a model to predict the δ2H and δ18O values of body water and a second model to predict the δ2H and δ18O values of hair. In contrast to previous human-based studies, use of nonhuman primates fed controlled diets allowed us to further constrain model parameter values and evaluate model predictions. Both models reliably predicted the δ2H and δ18O values of body water and of hair. Moreover, the isotope data allowed us to better quantify values for two critical variables in the models: the δ2H and δ18O values of gut water and the 18O isotope fractionation associated with a carbonyl oxygen-water interaction in the gut (αow). Our modeling efforts indicated that better predictions for body water and hair isotope values were achieved by making the isotopic composition of gut water approached that of body water. Additionally, the value of αow was 1.0164, in close agreement with the only other previously measured observation (microbial spore cell walls), suggesting robustness of this fractionation factor across different biological systems. PMID:22553163

  3. Hydrogen and oxygen isotope ratios in body water and hair: modeling isotope dynamics in nonhuman primates.

    PubMed

    O'Grady, Shannon P; Valenzuela, Luciano O; Remien, Christopher H; Enright, Lindsey E; Jorgensen, Matthew J; Kaplan, Jay R; Wagner, Janice D; Cerling, Thure E; Ehleringer, James R

    2012-07-01

    The stable isotopic composition of drinking water, diet, and atmospheric oxygen influence the isotopic composition of body water ((2)H/(1)H, (18)O/(16)O expressed as δ(2) H and δ(18)O). In turn, body water influences the isotopic composition of organic matter in tissues, such as hair and teeth, which are often used to reconstruct historical dietary and movement patterns of animals and humans. Here, we used a nonhuman primate system (Macaca fascicularis) to test the robustness of two different mechanistic stable isotope models: a model to predict the δ(2)H and δ(18)O values of body water and a second model to predict the δ(2)H and δ(18)O values of hair. In contrast to previous human-based studies, use of nonhuman primates fed controlled diets allowed us to further constrain model parameter values and evaluate model predictions. Both models reliably predicted the δ(2)H and δ(18)O values of body water and of hair. Moreover, the isotope data allowed us to better quantify values for two critical variables in the models: the δ(2)H and δ(18)O values of gut water and the (18)O isotope fractionation associated with a carbonyl oxygen-water interaction in the gut (α(ow)). Our modeling efforts indicated that better predictions for body water and hair isotope values were achieved by making the isotopic composition of gut water approached that of body water. Additionally, the value of α(ow) was 1.0164, in close agreement with the only other previously measured observation (microbial spore cell walls), suggesting robustness of this fractionation factor across different biological systems.

  4. Situs Inversus Totalis in Twins: A Brief Review and a Life History / Twin Research: Twin Studies of Trisomy 21; Monozygotic Twin Concordance for Bilateral Coronoid Hyperplasia; Prenatal Hormonal Effects in Mixed-Sex Non-Human Primate Litters; Insurance Mandates and Twinning After In Vitro Fertilization / News Reports: First Report of Identical Twin Puppies; Twins Sisters Turn 100; Remembering an Identical Twin Production Designer; New York City Marathon Quadruplets.

    PubMed

    Segal, Nancy L

    2017-02-01

    The presence of situs inversus totalis (full reversal of internal organs) in twins is briefly reviewed. Information gathered from 35-year-old monozygotic (MZ) female twin pair discordant for this condition is presented. This is followed by summaries of research on the frequency of trisomy 21 (Down syndrome) in twins, the first case of MZ twin concordance for bilateral coronoid hyperplasia, prenatal hormonal effects in mixed-sex non-human primate litters, and links between insurance mandates and twinning following in vitro fertilization. The final section of this article describes twin-related events reported in the news, namely, the first recorded birth of identical twin puppies; the 100th birthday celebration of a pair of fraternal female twins, the passing of an award-winning identical twin production designer, and the first running of the New York City Marathon by a set of quadruplets.

  5. Evaluation of transit-time and electromagnetic flow measurement in a chronically instrumented nonhuman primate model

    NASA Technical Reports Server (NTRS)

    Koenig, S. C.; Reister, C. A.; Schaub, J.; Swope, R. D.; Ewert, D.; Fanton, J. W.; Convertino, V. A. (Principal Investigator)

    1996-01-01

    The Physiology Research Branch at Brooks AFB conducts both human and nonhuman primate experiments to determine the effects of microgravity and hypergravity on the cardiovascular system and to identify the particular mechanisms that invoke these responses. Primary investigative efforts in our nonhuman primate model require the determination of total peripheral resistance, systemic arterial compliance, and pressure-volume loop characteristics. These calculations require beat-to-beat measurement of aortic flow. This study evaluated accuracy, linearity, biocompatability, and anatomical features of commercially available electromagnetic (EMF) and transit-time flow measurement techniques. Five rhesus monkeys were instrumented with either EMF (3 subjects) or transit-time (2 subjects) flow sensors encircling the proximal ascending aorta. Cardiac outputs computed from these transducers taken over ranges of 0.5 to 2.0 L/min were compared to values obtained using thermodilution. In vivo experiments demonstrated that the EMF probe produced an average error of 15% (r = .896) and 8.6% average linearity per reading, and the transit-time flow probe produced an average error of 6% (r = .955) and 5.3% average linearity per reading. Postoperative performance and biocompatability of the probes were maintained throughout the study. The transit-time sensors provided the advantages of greater accuracy, smaller size, and lighter weight than the EMF probes. In conclusion, the characteristic features and performance of the transit-time sensors were superior to those of the EMF sensors in this study.

  6. Evaluation of transit-time and electromagnetic flow measurement in a chronically instrumented nonhuman primate model.

    PubMed

    Koenig, S C; Reister, C A; Schaub, J; Swope, R D; Ewert, D; Fanton, J W

    1996-01-01

    The Physiology Research Branch at Brooks AFB conducts both human and nonhuman primate experiments to determine the effects of microgravity and hypergravity on the cardiovascular system and to identify the particular mechanisms that invoke these responses. Primary investigative efforts in our nonhuman primate model require the determination of total peripheral resistance, systemic arterial compliance, and pressure-volume loop characteristics. These calculations require beat-to-beat measurement of aortic flow. This study evaluated accuracy, linearity, biocompatability, and anatomical features of commercially available electromagnetic (EMF) and transit-time flow measurement techniques. Five rhesus monkeys were instrumented with either EMF (3 subjects) or transit-time (2 subjects) flow sensors encircling the proximal ascending aorta. Cardiac outputs computed from these transducers taken over ranges of 0.5 to 2.0 L/min were compared to values obtained using thermodilution. In vivo experiments demonstrated that the EMF probe produced an average error of 15% (r = .896) and 8.6% average linearity per reading, and the transit-time flow probe produced an average error of 6% (r = .955) and 5.3% average linearity per reading. Postoperative performance and biocompatability of the probes were maintained throughout the study. The transit-time sensors provided the advantages of greater accuracy, smaller size, and lighter weight than the EMF probes. In conclusion, the characteristic features and performance of the transit-time sensors were superior to those of the EMF sensors in this study.

  7. From Sweeping to the Caress: Similarities and Discrepancies between Human and Non-Human Primates’ Pleasant Touch

    PubMed Central

    Grandi, Laura C.

    2016-01-01

    Affective touch plays a key role in affiliative behavior, offering a mechanism for the formation and maintenance of social bonds among conspecifics, both in humans and non-human primates. Furthermore, it has been speculated that the CT fiber system is a specific coding channel for affiliative touch that occurs during skin-to-skin interactions with conspecifics. In humans, this touch is commonly referred to as the caress, and its correlation with the CT fiber system has been widely demonstrated. It has been hypothesized that the sweeping touch that occurs during grooming in non-human primates may modulate the CT fibers, with recent preliminary studies on rhesus monkeys supporting this hypothesis. The present mini-review proposes a comparison between the pleasant touch, caress and sweeping of humans and non-human primates, respectively. The currently available data was therefore reviewed regarding (i) the correlation between pleasant touch and CT fibers both in humans and non-human primates, (ii) the autonomic effects, (iii) the encoding at the central nervous system, (iv) the development from early life to adulthood, and (v) the potential applications of pleasant touch in the daily lives of both humans and non-human primates. Moreover, by considering both the similarities and discrepancies between the human caress and non-human primate sweeping, a possible evolutionary mechanism can be proposed that has developed from sweeping as a utilitarian action with affiliative meaning among monkeys, to the caress as a purely affective gesture associated with humans. PMID:27660620

  8. In a non-human primate model, aging disrupts the neural control of intestinal smooth muscle contractility in a region-specific manner

    PubMed Central

    Tran, L; Greenwood-Van Meerveld, B

    2014-01-01

    Background Incidences of gastrointestinal (GI) motility disorders increase with age. However, there is a paucity of knowledge about the aging mechanisms leading to GI dysmotility. Motility in the GI tract is a function of smooth muscle contractility, which is modulated in part by the enteric nervous system (ENS). Evidence suggests that aging impairs the ENS, thus we tested the hypothesis that senescence in the GI tract precipitates abnormalities in smooth muscle and neurally mediated contractility in a region-specific manner. Methods Jejunal and colonic circular muscle strips were isolated from young (4–10 years) and old (18+ years) baboons. Myogenic responses were investigated using potassium chloride (KCl) and carbachol (CCh). Neurally mediated contractile responses were evoked by electrical field stimulation (EFS) and were recorded in the absence and presence of atropine (1 μM) or NG-Nitro-l-arginine methyl ester (l-NAME; 100 μM). Key Results The myogenic responses to KCl in the jejunum and colon were unaffected by age. In the colon, but not the jejunum, CCh-induced contractile responses were reduced in aged animals. Compared to young baboons, there was enhanced EFS-induced contractility of old baboon jejunal smooth muscle in contrast to the reduced contractility in the colon. The effect of atropine on the EFS response was lower in aged colonic tissue, suggesting reduced participation of acetylcholine. In aged jejunal tissue, higher contractile responses to EFS were found to be due to reduced nitregic inhibition. Conclusions & Inferences These findings provide key evidence for the importance of intestinal smooth muscle and ENS senescence in age-associated GI motility disorders. PMID:24548258

  9. The marmoset as a model for the study of primate parental behavior.

    PubMed

    Saito, Atsuko

    2015-04-01

    Parental behavior is important for the development of mammalian offspring. Research on the mechanisms underlying parental behavior, however, has been largely restricted to rodent models. As a consequence, although research on parent-infant relationships has been conducted using macaque monkeys for more than half a century, little is known about the neural mechanisms and brain regions associated with such behaviors in primates. This article reviews parental behavior and its endocrinological mechanisms in marmosets and tamarins, both cooperative breeders in the callitrichid family, and compares these findings with studies of macaque monkeys. The paper examines the similarities and differences between marmosets and humans, and suggests the possibility that marmosets can be a model for future studies of the neural underpinnings and endocrinology underlying human parental behavior.

  10. Procedures for mucosal immunization and analyses of cellular immune response to candidate HIV vaccines in murine and nonhuman primate models.

    PubMed

    Singh, Shailbala; Nehete, Pramod; Hanley, Patrick; Nehete, Bharti; Yang, Guojun; He, Hong; Anthony, Scott M; Schluns, Kimberly S; Sastry, K Jagannadha

    2014-01-01

    Sampling the mucosal tissues and analyses of immune responses are integral to vaccine-development strategies against human immunodeficiency virus (HIV), which is transmitted predominantly across the oro-genital mucosa. While immune assay development and standardization attempts employ mouse models, immunogenicity and protective efficacy that can be extrapolated to humans are realized only from experiments in nonhuman primates. Here, we describe commonly used practices for immunizations in rhesus macaques (Macaca mulatta) along with procedures for obtaining important mucosal tissues samples from macaques and mice. We also describe detailed protocols for two important assays applicable in mouse as well as primate experiments for determining antigen-specific T cells responses induced after vaccination.

  11. Primate cognition.

    PubMed

    Seed, Amanda; Tomasello, Michael

    2010-07-01

    As the cognitive revolution was slow to come to the study of animal behavior, the vast majority of what we know about primate cognition has been discovered in the last 30 years. Building on the recognition that the physical and social worlds of humans and their living primate relatives pose many of the same evolutionary challenges, programs of research have established that the most basic cognitive skills and mental representations that humans use to navigate those worlds are already possessed by other primates. There may be differences between humans and other primates, however, in more complex cognitive skills, such as reasoning about relations, causality, time, and other minds. Of special importance, the human primate seems to possess a species-unique set of adaptations for "cultural intelligence," which are broad reaching in their effects on human cognition.

  12. Touchscreen-based cognitive tasks reveal age-related impairment in a primate aging model, the grey mouse lemur (Microcebus murinus).

    PubMed

    Joly, Marine; Ammersdörfer, Sandra; Schmidtke, Daniel; Zimmermann, Elke

    2014-01-01

    Mouse lemurs are suggested to represent promising novel non-human primate models for aging research. However, standardized and cross-taxa cognitive testing methods are still lacking. Touchscreen-based testing procedures have proven high stimulus control and reliability in humans and rodents. The aim of this study was to adapt these procedures to mouse lemurs, thereby exploring the effect of age. We measured appetitive learning and cognitive flexibility of two age groups by applying pairwise visual discrimination (PD) and reversal learning (PDR) tasks. On average, mouse lemurs needed 24 days of training before starting with the PD task. Individual performances in PD and PDR tasks correlate significantly, suggesting that individual learning performance is unrelated to the respective task. Compared to the young, aged mouse lemurs showed impairments in both PD and PDR tasks. They needed significantly more trials to reach the task criteria. A much higher inter-individual variation in old than in young adults was revealed. Furthermore, in the PDR task, we found a significantly higher perseverance in aged compared to young adults, indicating an age-related deficit in cognitive flexibility. This study presents the first touchscreen-based data on the cognitive skills and age-related dysfunction in mouse lemurs and provides a unique basis to study mechanisms of inter-individual variation. It furthermore opens exciting perspectives for comparative approaches in aging, personality, and evolutionary research.

  13. Fluid and electrolyte homeostasis in space - A primate model to look at mechanisms

    NASA Technical Reports Server (NTRS)

    Moore-Ede, M. C.; Churchill, S. E.; Leach, C. S.; Sulzman, F. M.; Fuller, C. A.; Kass, D.

    1982-01-01

    To elucidate the physiological mechanisms involved in the cardiovascular and renal responses to spaceflight, a ground-based primate model has been developed which uses lower body positive pressure (LBPP) to simulate the chronic central vascular expansion associated with weightlessnes. Four male squirrel monkeys with chronically implanted arterial and venous catheters and the capacity for continuous urine collection were subjected to LBPP for 4 days. Onset of LBPP resulted in an immediate diuresis, natriuresis and kaliuresis and a significant fall in plasma aldosterone and potassium levels. By day 2 the level of natriuresis had decreased by half, while potassium excretion and plasma aldosterone values had returned to control levels despite the persistence of a significantly reduced plasma potassium concentration. It is concluded that the low plasma potassium level appears not to stimulate a compensatory fall in plasma aldosterone because of the simultaneous presence of body volume contraction acting to raise aldosterone levels.

  14. Estimating thumb-index finger precision grip and manipulation potential in extant and fossil primates.

    PubMed

    Feix, Thomas; Kivell, Tracy L; Pouydebat, Emmanuelle; Dollar, Aaron M

    2015-05-06

    Primates, and particularly humans, are characterized by superior manual dexterity compared with other mammals. However, drawing the biomechanical link between hand morphology/behaviour and functional capabilities in non-human primates and fossil taxa has been challenging. We present a kinematic model of thumb-index precision grip and manipulative movement based on bony hand morphology in a broad sample of extant primates and fossil hominins. The model reveals that both joint mobility and digit proportions (scaled to hand size) are critical for determining precision grip and manipulation potential, but that having either a long thumb or great joint mobility alone does not necessarily yield high precision manipulation. The results suggest even the oldest available fossil hominins may have shared comparable precision grip manipulation with modern humans. In particular, the predicted human-like precision manipulation of Australopithecus afarensis, approximately one million years before the first stone tools, supports controversial archaeological evidence of tool-use in this taxon.

  15. Estimating thumb–index finger precision grip and manipulation potential in extant and fossil primates

    PubMed Central

    Feix, Thomas; Kivell, Tracy L.; Pouydebat, Emmanuelle; Dollar, Aaron M.

    2015-01-01

    Primates, and particularly humans, are characterized by superior manual dexterity compared with other mammals. However, drawing the biomechanical link between hand morphology/behaviour and functional capabilities in non-human primates and fossil taxa has been challenging. We present a kinematic model of thumb–index precision grip and manipulative movement based on bony hand morphology in a broad sample of extant primates and fossil hominins. The model reveals that both joint mobility and digit proportions (scaled to hand size) are critical for determining precision grip and manipulation potential, but that having either a long thumb or great joint mobility alone does not necessarily yield high precision manipulation. The results suggest even the oldest available fossil hominins may have shared comparable precision grip manipulation with modern humans. In particular, the predicted human-like precision manipulation of Australopithecus afarensis, approximately one million years before the first stone tools, supports controversial archaeological evidence of tool-use in this taxon. PMID:25878134

  16. Micronucleated erythrocyte frequencies in old and new world primates: measurement of micronucleated erythrocyte frequencies in peripheral blood of Callithrix jacchus as a model for evaluating genotoxicity in primates.

    PubMed

    Zúñiga-González, Guillermo M; Gómez-Meda, Belinda C; Zamora-Perez, Ana L; Ramos-Ibarra, M Luisa; Batista-González, Cecilia M; Lemus-Varela, M Lourdes; Rodríguez-Avila, J Luis; Gallegos-Arreola, Martha P

    2005-12-01

    Nonhuman primates are of particular relevance in evaluating the potential toxicity of drugs and environmental agents. We have used previously published information and data from the present study to establish a relationship for New World (NW) and Old World (OW) primates on the basis of the frequency of spontaneous micronucleated erythrocytes (MNEs) observed in peripheral blood. Data on spontaneous MNEs in peripheral blood from 15 species of primates, including humans, indicate that NW primates have significantly (P < 0.01) higher MNE frequencies (group mean, 9.5 +/- 7.3 MNEs/10,000 erythrocytes; range, 0.7-20.5/10,000 erythrocytes) than OW primates (group mean, 1.0 +/- 0.9 MNEs/10,000 erythrocytes; range, 0.0-2.6 MNEs/10,000 erythrocytes). Humans are believed to have developed in the OW, and human MNE frequencies were similar to those described for OW primate species. We selected the common marmoset (Callithrix jacchus), a NW primate, to determine whether therapeutic pediatric doses of Metotrexate (MTX; 2.5 mg/kg), Cyclophosphamide (CP; 5 mg/kg), Cytosine-arabinoside (Ara-C; 3 mg/kg), or 5-Fluorouracil (5-FU; 10 mg/kg), administered daily for two consecutive days, increase the frequency of micronuclei. Micronucleated polychromatic erythrocyte frequencies were increased significantly in groups receiving MTX, CP and Ara-C, while MNE frequencies were increased by the Ara-C treatment. The results of this study indicate that NW primates have higher spontaneous MNE frequencies than OW primates, and because of this, NW primates like the common marmoset, may be suitable for evaluating the genotoxicity of chemical agents.

  17. Comparative Host Response of 2 Human Acellular Dermal Matrices in a Primate Implant Model

    PubMed Central

    Sandor, Maryellen; Singh, Devinder; Silverman, Ronald P.; Xu, Hui; De Deyne, Patrick G.

    2014-01-01

    Objective: We examined the differences in capsule formation between 2 commercially available human acellular dermal matrices in a nonhuman primate model. Methods: Primates were implanted dorsally with a subcutaneously placed tissue expander and randomized into 3 groups, receiving skin coverage only, coverage with non-irradiated freeze-dried human acellular dermal matrix, or coverage with gamma-irradiated human acellular dermal matrix. After 9 weeks, soft tissue around the tissue expander was excised and evaluated qualitatively and quantitatively to assess extent of inflammation (CD68 antibodies and interleukin-6 levels), degradation and fibrosis (matrix metalloproteinase-1 and procollagen-1 staining), and mechanical (tensile) strength. Results: Histological evaluation of tissue around the tissue expander indicated differences in host response, suggesting capsule presence in the gamma-irradiated matrix group but not the freeze-dried matrix group. The extent of local inflammation was much higher in the gamma-irradiated matrix group which demonstrated mean (standard deviation) localized interleukin-6 concentration of 67.3 (53.6) vs 16.3 (6.7) pg/mg protein in the non-irradiated matrix group. There was robust degradation and fibrotic response in the gamma-irradiated matrix group versus the freeze-dried matrix group. Mechanical testing indicated mean (standard deviation) ultimate tensile strength of 12.0 (7.1) N in the gamma-irradiated matrix group versus 99.3 (48.8) N in the freeze-dried matrix group. Conclusions: Enclosure of a tissue expander with human acellular dermal matrix untreated by gamma irradiation led to minimal inflammation and minimal evidence of fibrosis/capsule around the tissue expander compared with robust capsule formation around the tissue expander that was covered by a gamma-irradiated human acellular dermal matrix. PMID:24570768

  18. Assessment of Foraging Devices as a Model for Decision-Making in Nonhuman Primate Environmental Enrichment

    PubMed Central

    Bennett, Allyson J; Perkins, Chaney M; Harty, Nicole M; Niu, Mengyao; Buelo, Audrey K; Luck, Melissa L; Pierre, Peter J

    2014-01-01

    Continued progress to move evidence-based best practices into community and regulatory animal welfare standards depends in part on developing common metrics to assess cost, benefit, and relative value. Here we describe a model approach to evidence-based evaluation and an example of comprehensive cost–benefit assessment for a common element of environmental enrichment plans for laboratory-housed nonhuman primates. Foraging devices encourage a species-typical activity that dominates the time budget of primates outside captivity and provide inherent cognitive challenges, physical activity demands, and multi-sensory stimulation. However, their implementation is not standard, and is challenged by perception of high costs and labor; nutritional and health concerns; and identification of best practices in implementation (that is, device types, food type, frequency of delivery and rotation). To address these issues, we directly compared monkeys’ engagement with different foraging devices and the comprehensive cost of implementing foraging opportunities. We recorded 14 adult male cynomolgus monkeys’ interactions with 7 types of devices filled with a range of enrichment foods. All devices elicited foraging behavior, but there were significant differences among them both initially and over subsequent observations. Devices that afforded opportunity for extraction of small food items and that posed manipulative challenge elicited greater manipulation. The cost of providing a foraging opportunity to a single monkey is roughly US$1, with approximately 80% attributable to labor. This study is the first to perform a rigorous cost–benefit analysis and comparison of common foraging devices included in environmental enrichment. Its broader significance lies in its contribution to the development of methods to facilitate improvement in evidence-based practices and common standards to enhance laboratory animal welfare. PMID:25255067

  19. Neanderthal taxonomy reconsidered: Implications of 3D primate models of intra- and interspecific differences

    PubMed Central

    Harvati, Katerina; Frost, Stephen R.; McNulty, Kieran P.

    2004-01-01

    The taxonomic status of Neanderthals lies at the center of the modern human origins debate. Proponents of the single-origin model often view this group as a distinct species with little or no contribution to the evolution of modern humans. Adherents to the regional continuity model consider Neanderthals a subspecies or population of Homo sapiens, which contributed significantly to the evolution of early modern Europeans. Paleontologists generally agree that fossil species should be equivalent to extant ones in the amount of their morphological variation. Recognition of fossil species therefore hinges on analogy to living species. A previous study by one of the authors and recent work by other researchers [Schillachi, M. A. & Froelich, J. W. (2001) Am. J. Phys. Anthropol. 115, 157–166] have supported specific status for Neanderthals based on analogy to chimpanzees and Sulawesi macaques, respectively. However, these taxa may not be the most appropriate models for Pleistocene humans. Here we test the hypothesis that Neanderthals represent a subspecies of H. sapiens by comparing the degree of their morphological differentiation from modern humans to that found within and between 12 species of extant primates. The model taxa comprised >1,000 specimens, including phylogenetic (modern humans and African apes) and ecological (eight papionin taxa) models for Pleistocene humans. Morphological distances between model taxon pairs were compared to the distances between Neanderthals and modern humans obtained by using a randomization technique. Results strongly support a specific distinction for Neanderthals. PMID:14745010

  20. Nonhuman Primate Models of Depression: Effects of Early Experience and Stress

    PubMed Central

    Worlein, Julie M.

    2014-01-01

    Depression causes significant morbidity in the human population. The Diathesis-Stress/Two-Hit model of depression hypothesizes that stress interacts with underlying (probably genetic) predispositions to produce a central nervous system that is primed to express psychopathology when confronted with stressful experiences later in life. Nonhuman primate (NHP) studies have been extensively utilized to test this model. NHPs are especially useful for studying effects of early experience, because many aspects of NHP infancy are similar to humans, whereas development occurs at an accelerated rate and therefore allows for more rapid assessment of experimental variables. In addition, the ability to manipulate putative risk factors, including introducing experimental stress during development, allows inference of causality not possible with human studies. This manuscript reviews experimental paradigms that have been utilized to model early adverse experience in NHPs, including peer-rearing, maternal separation, and variable foraging. It also provides examples of how this model has been used to investigate the effects of early experience on later neurobiology, physiology, and behavior associated with depression. We conclude that the NHP offers an excellent model to research mechanisms contributing to the Diathesis-Stress/Two-Hit model of depression. PMID:25225305

  1. A simpler primate brain: the visual system of the marmoset monkey

    PubMed Central

    Solomon, Samuel G.; Rosa, Marcello G. P.

    2014-01-01

    Humans are diurnal primates with high visual acuity at the center of gaze. Although primates share many similarities in the organization of their visual centers with other mammals, and even other species of vertebrates, their visual pathways also show unique features, particularly with respect to the organization of the cerebral cortex. Therefore, in order to understand some aspects of human visual function, we need to study non-human primate brains. Which species is the most appropriate model? Macaque monkeys, the most widely used non-human primates, are not an optimal choice in many practical respects. For example, much of the macaque cerebral cortex is buried within sulci, and is therefore inaccessible to many imaging techniques, and the postnatal development and lifespan of macaques are prohibitively long for many studies of brain maturation, plasticity, and aging. In these and several other respects the marmoset, a small New World monkey, represents a more appropriate choice. Here we review the visual pathways of the marmoset, highlighting recent work that brings these advantages into focus, and identify where additional work needs to be done to link marmoset brain organization to that of macaques and humans. We will argue that the marmoset monkey provides a good subject for studies of a complex visual system, which will likely allow an important bridge linking experiments in animal models to humans. PMID:25152716

  2. A simpler primate brain: the visual system of the marmoset monkey.

    PubMed

    Solomon, Samuel G; Rosa, Marcello G P

    2014-01-01

    Humans are diurnal primates with high visual acuity at the center of gaze. Although primates share many similarities in the organization of their visual centers with other mammals, and even other species of vertebrates, their visual pathways also show unique features, particularly with respect to the organization of the cerebral cortex. Therefore, in order to understand some aspects of human visual function, we need to study non-human primate brains. Which species is the most appropriate model? Macaque monkeys, the most widely used non-human primates, are not an optimal choice in many practical respects. For example, much of the macaque cerebral cortex is buried within sulci, and is therefore inaccessible to many imaging techniques, and the postnatal development and lifespan of macaques are prohibitively long for many studies of brain maturation, plasticity, and aging. In these and several other respects the marmoset, a small New World monkey, represents a more appropriate choice. Here we review the visual pathways of the marmoset, highlighting recent work that brings these advantages into focus, and identify where additional work needs to be done to link marmoset brain organization to that of macaques and humans. We will argue that the marmoset monkey provides a good subject for studies of a complex visual system, which will likely allow an important bridge linking experiments in animal models to humans.

  3. The primate autoimmune encephalomyelitis model; a bridge between mouse and man

    PubMed Central

    ‘t Hart, Bert A; van Kooyk, Yvette; Geurts, Jeroen J G; Gran, Bruno

    2015-01-01

    Introduction Multiple sclerosis (MS) is an enigmatic autoimmune-driven inflammatory/demyelinating disease of the human central nervous system (CNS), affecting brain, spinal cord, and optic nerves. The cause of the disease is not known and the number of effective treatments is limited. Despite some clear successes, translation of immunological discoveries in the mouse experimental autoimmune encephalomyelitis (EAE) model into effective therapies for MS patients has been difficult. This translation gap between MS and its elected EAE animal model reflects the phylogenetic distance between humans and their experimental counterpart, the inbred/specific pathogen free (SPF) laboratory mouse. Objective Here, we discuss that important new insights can be obtained into the mechanistic basis of the therapy paradox from the study of nonhuman primate EAE (NHP-EAE) models, the well-validated EAE model in common marmosets (Callithrix jacchus) in particular. Interpretation Data presented in this review demonstrate that due to a considerable immunological and pathological overlap with mouse EAE on one side and MS on the other, the NHP EAE model can help us bridge the translation gap. PMID:26000330

  4. Progress and Prospects for Genetic Modification of Nonhuman Primate Models in Biomedical Research

    PubMed Central

    Chan, Anthony W. S.

    2013-01-01

    The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and new therapies for many diseases. Biomedical research has not been the primary role of NHPs. They have mainly been used for safety evaluation and pharmacokinetics studies, rather than determining therapeutic efficacy. The development of the first transgenic rhesus macaque (2001) revolutionized the role of NHP models in biomedicine. Development of the transgenic NHP model of Huntington's disease (2008), with distinctive clinical features, further suggested the uniqueness of the model system; and the potential role of the NHP model for human genetic disorders. Modeling human genetic diseases using NHPs will continue to thrive because of the latest advances in molecular, genetic, and embryo technologies. NHPs rising role in biomedical research, specifically pre-clinical studies, is foreseeable. The path toward the development of transgenic NHPs and the prospect of transgenic NHPs in their new role in future biomedicine needs to be reviewed. This article will focus on the advancement of transgenic NHPs in the past decade, including transgenic technologies and disease modeling. It will outline new technologies that may have significant impact in future NHP modeling and will conclude with a discussion of the future prospects of the transgenic NHP model. PMID:24174443

  5. Progress and prospects for genetic modification of nonhuman primate models in biomedical research.

    PubMed

    Chan, Anthony W S

    2013-01-01

    The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and new therapies for many diseases. Biomedical research has not been the primary role of NHPs. They have mainly been used for safety evaluation and pharmacokinetics studies, rather than determining therapeutic efficacy. The development of the first transgenic rhesus macaque (2001) revolutionized the role of NHP models in biomedicine. Development of the transgenic NHP model of Huntington's disease (2008), with distinctive clinical features, further suggested the uniqueness of the model system; and the potential role of the NHP model for human genetic disorders. Modeling human genetic diseases using NHPs will continue to thrive because of the latest advances in molecular, genetic, and embryo technologies. NHPs rising role in biomedical research, specifically pre-clinical studies, is foreseeable. The path toward the development of transgenic NHPs and the prospect of transgenic NHPs in their new role in future biomedicine needs to be reviewed. This article will focus on the advancement of transgenic NHPs in the past decade, including transgenic technologies and disease modeling. It will outline new technologies that may have significant impact in future NHP modeling and will conclude with a discussion of the future prospects of the transgenic NHP model.

  6. A Novel Nonhuman Primate Model of Cigarette Smoke–Induced Airway Disease

    PubMed Central

    Polverino, Francesca; Doyle-Eisele, Melanie; McDonald, Jacob; Wilder, Julie A.; Royer, Christopher; Laucho-Contreras, Maria; Kelly, Emer M.; Divo, Miguel; Pinto-Plata, Victor; Mauderly, Joe; Celli, Bartolome R.; Tesfaigzi, Yohannes; Owen, Caroline A.

    2016-01-01

    Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)–exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD. PMID:25542772

  7. Development of a Novel Nonhuman Primate Model for Rift Valley Fever

    PubMed Central

    Bird, Brian H.; Lewis, Bridget; Johnston, Sara C.; McCarthy, Sarah; Keeney, Ashley; Botto, Miriam; Donnelly, Ginger; Shamblin, Joshua; Albariño, César G.; Nichol, Stuart T.; Hensley, Lisa E.

    2012-01-01

    Rift Valley fever (RVF) virus (RVFV) can cause severe human disease characterized by either acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. The existing nonhuman primate (NHP) model for RVF utilizes an intravenous (i.v.) exposure route in rhesus macaques (Macaca mulatta). Severe disease in these animals is infrequent, and large cohorts are needed to observe significant morbidity and mortality. To overcome these drawbacks, we evaluated the infectivity and pathogenicity of RVFV in the common marmoset (Callithrix jacchus) by i.v., subcutaneous (s.c.), and intranasal exposure routes to more closely mimic natural exposure. Marmosets were more susceptible to RVFV than rhesus macaques and experienced higher rates of morbidity, mortality, and viremia and marked aberrations in hematological and chemistry values. An overwhelming infection of hepatocytes was a major consequence of infection of marmosets by the i.v. and s.c. exposure routes. Additionally, these animals displayed signs of hemorrhagic manifestations and neurological impairment. Based on our results, the common marmoset model more closely resembles severe human RVF disease and is therefore an ideal model for the evaluation of potential vaccines and therapeutics. PMID:22156530

  8. Stimulant and motivational effects of alcohol: lessons from rodent and primate models.

    PubMed

    Brabant, Christian; Guarnieri, Douglas J; Quertemont, Etienne

    2014-07-01

    In several animal species including humans, the acute administration of low doses of alcohol increases motor activity. Different theories have postulated that alcohol-induced hyperactivity is causally related to alcoholism. Moreover, a common biological mechanism in the mesolimbic dopamine system has been proposed to mediate the stimulant and motivational effects of alcohol. Numerous studies have examined whether alcohol-induced hyperactivity is related to alcoholism using a great variety of animal models and several animal species. However, there is no review that has summarized this extensive literature. In this article, we present the various experimental models that have been used to study the relationship between the stimulant and motivational effects of alcohol in rodents and primates. Furthermore, we discuss whether the theories hypothesizing a causal link between alcohol-induced hyperactivity and alcoholism are supported by published results. The reviewed findings indicate that animal species that are stimulated by alcohol also exhibit alcohol preference. Additionally, the role of dopamine in alcohol-induced hyperactivity is well established since blocking dopaminergic activity suppresses the stimulant effects of alcohol. However, dopamine transmission plays a much more complex function in the motivational properties of alcohol and the neuronal mechanisms involved in alcohol stimulation and reward are distinct. Overall, the current review provides mixed support for theories suggesting that the stimulant effects of alcohol are related to alcoholism and highlights the importance of animal models as a way to gain insight into alcoholism.

  9. Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection.

    PubMed

    Geisbert, Thomas W; Strong, James E; Feldmann, Heinz

    2015-10-01

    The filoviruses, Ebola virus and Marburg virus, are zoonotic pathogens that cause severe hemorrhagic fever in humans and nonhuman primates (NHPs), with case-fatality rates ranging from 23% to 90%. The current outbreak of Ebola virus infection in West Africa, with >26 000 cases, demonstrates the long-underestimated public health danger that filoviruses pose as natural human pathogens. Currently, there are no vaccines or treatments licensed for human use. Licensure of any medical countermeasure may require demonstration of efficacy in the gold standard cynomolgus or rhesus macaque models of filovirus infection. Substantial progress has been made over the last decade in characterizing the filovirus NHP models. However, there is considerable debate over a variety of experimental conditions, including differences among filovirus isolates used, routes and doses of exposure, and euthanasia criteria, all of which may contribute to variability of results among different laboratories. As an example of the importance of understanding these differences, recent data with Ebola virus shows that an addition of a single uridine residue in the glycoprotein gene at the editing site attenuates the virus. Here, we draw on decades of experience working with filovirus-infected NHPs to provide a perspective on the importance of various experimental conditions.

  10. Sequence and diversity of DRB genes of Aotus nancymaae, a primate model for human malaria parasites.

    PubMed

    Nino-Vasquez, J J; Vogel, D; Rodriguez, R; Moreno, A; Patarroyo, M E; Pluschke, G; Daubenberger, C A

    2000-03-01

    The New World primate Aotus nancymaae is susceptible to infection with the human malaria parasite Plasmodium falciparum and Plasmodium vivax and has therefore been recommended by the World Health Organization as a model for evaluation of malaria vaccine candidates. We present here a first step in the molecular characterization of the major histocompatibility complex (MHC) class II DRB genes of Aotus nancymaae (owl monkey or night monkey) by nucleotide sequence analysis of the polymorphic exon 2 segments. In a group of 15 nonrelated animals captivated in the wild, 34 MHC DRB alleles could be identified. Six allelic lineages were detected, two of them having human counterparts, while two other lineages have not been described in any other New World monkey species studied. As in the common marmoset, the diversity of DRB alleles appears to have arisen largely by point mutations in the beta-pleated sheets and by frequent exchange of fixed sequence motifs in the alpha-helical portion. Pairs of alleles differing only at amino acid position b86 by an exchange of valine to glycine are present in Aotus, as in humans. Essential amino acid residues contributing to MHC DR peptide binding pockets number 1 and 4 are conserved or semiconserved between HLA-DR and Aona-DRB molecules, indicating a capacity to bind similar peptide repertoires. These results support fully our using Aotus monkeys as an animal model for evaluation of future subunit vaccine candidates.

  11. Genomic Variants Associated with Resistance to High Fat Diet Induced Obesity in a Primate Model

    PubMed Central

    Harris, R. Alan; Alcott, Callison E.; Sullivan, Elinor L.; Takahashi, Diana; McCurdy, Carrie E.; Comstock, Sarah; Baquero, Karalee; Blundell, Peter; Frias, Antonio E.; Kahr, Maike; Suter, Melissa; Wesolowski, Stephanie; Friedman, Jacob E.; Grove, Kevin L.; Aagaard, Kjersti M.

    2016-01-01

    Maternal obesity contributes to an increased risk of lifelong morbidity and mortality for both the mother and her offspring. In order to better understand the molecular mechanisms underlying these risks, we previously established and extensively characterized a primate model in Macaca fuscata (Japanese macaque). In prior studies we have demonstrated that a high fat, caloric dense maternal diet structures the offspring’s epigenome, metabolome, and intestinal microbiome. During the course of this work we have consistently observed that a 36% fat diet leads to obesity in the majority, but not all, of exposed dams. In the current study, we sought to identify the genomic loci rendering resistance to obesity despite chronic consumption of a high fat diet in macaque dams. Through extensive phenotyping together with exon capture array and targeted resequencing, we identified three novel single nucleotide polymorphisms (SNPs), two in apolipoprotein B (APOB) and one in phospholipase A2 (PLA2G4A) that significantly associated with persistent weight stability and insulin sensitivity in lean macaques. By application of explicit orthogonal modeling (NOIA), we estimated the polygenic and interactive nature of these loci against multiple metabolic traits and their measures (i.e., serum LDL levels) which collectively render an obesity resistant phenotype in our adult female dams. PMID:27811965

  12. In vivo bone strain and finite-element modeling of the craniofacial haft in catarrhine primates

    PubMed Central

    Ross, Callum F; Berthaume, Michael A; Dechow, Paul C; Iriarte-Diaz, Jose; Porro, Laura B; Richmond, Brian G; Spencer, Mark; Strait, David

    2011-01-01

    Hypotheses regarding patterns of stress, strain and deformation in the craniofacial skeleton are central to adaptive explanations for the evolution of primate craniofacial form. The complexity of craniofacial skeletal morphology makes it difficult to evaluate these hypotheses with in vivo bone strain data. In this paper, new in vivo bone strain data from the intraorbital surfaces of the supraorbital torus, postorbital bar and postorbital septum, the anterior surface of the postorbital bar, and the anterior root of the zygoma are combined with published data from the supraorbital region and zygomatic arch to evaluate the validity of a finite-element model (FEM) of a macaque cranium during mastication. The behavior of this model is then used to test hypotheses regarding the overall deformation regime in the craniofacial haft of macaques. This FEM constitutes a hypothesis regarding deformation of the facial skeleton during mastication. A simplified verbal description of the deformation regime in the macaque FEM is as follows. Inferior bending and twisting of the zygomatic arches about a rostrocaudal axis exerts inferolaterally directed tensile forces on the lateral orbital wall, bending the wall and the supraorbital torus in frontal planes and bending and shearing the infraorbital region and anterior zygoma root in frontal planes. Similar deformation regimes also characterize the crania of Homo and Gorilla under in vitro loading conditions and may be shared among extant catarrhines. Relatively high strain magnitudes in the anterior root of the zygoma suggest that the morphology of this region may be important for resisting forces generated during feeding. PMID:21105871

  13. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    SciTech Connect

    Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro; and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  14. Ethics of primate use

    NASA Astrophysics Data System (ADS)

    Prescott, M. J.

    2010-11-01

    This article provides an overview of the ethical issues raised by the use of non-human primates (NHPs) in research involving scientific procedures which may cause pain, suffering, distress or lasting harm. It is not an exhaustive review of the literature and views on this subject, and it does not present any conclusions about the moral acceptability or otherwise of NHP research. Rather the aim has been to identify the ethical issues involved and to provide guidance on how these might be addressed, in particular by carefully examining the scientific rationale for NHP use, implementing fully the 3Rs principle of Russell and Burch (1959) and applying a robust "harm-benefit assessment" to research proposals involving NHPs.

  15. Electric Field Model of Transcranial Electric Stimulation in Nonhuman Primates: Correspondence to Individual Motor Threshold

    PubMed Central

    Lee, Won Hee; Lisanby, Sarah H.; Laine, Andrew F.

    2015-01-01

    Objective To develop a pipeline for realistic head models of nonhuman primates (NHPs) for simulations of noninvasive brain stimulation, and use these models together with empirical threshold measurements to demonstrate that the models capture individual anatomical variability. Methods Based on structural MRI data, we created models of the electric field (E-field) induced by right unilateral (RUL) electroconvulsive therapy (ECT) in four rhesus macaques. Individual motor threshold (MT) was measured with transcranial electric stimulation (TES) administered through the RUL electrodes in the same subjects. Results The interindividual anatomical differences resulted in 57% variation in median E-field strength in the brain at fixed stimulus current amplitude. Individualization of the stimulus current by MT reduced the E-field variation in the target motor area by 27%. There was significant correlation between the measured MT and the ratio of simulated electrode current and E-field strength (r2 = 0.95, p = 0.026). Exploratory analysis revealed significant correlations of this ratio with anatomical parameters including of the superior electrode-to-cortex distance, vertex-to-cortex distance, and brain volume (r2 > 0.96, p < 0.02). The neural activation threshold was estimated to be 0.45 ± 0.07 V/cm for 0.2 ms stimulus pulse width. Conclusion These results suggest that our individual-specific NHP E-field models appropriately capture individual anatomical variability relevant to the dosing of TES/ECT. These findings are exploratory due to the small number of subjects. Significance This work can contribute insight in NHP studies of ECT and other brain stimulation interventions, help link the results to clinical studies, and ultimately lead to more rational brain stimulation dosing paradigms. PMID:25910001

  16. A Unified Model of Heading and Path Perception in Primate MSTd

    PubMed Central

    Layton, Oliver W.; Browning, N. Andrew

    2014-01-01

    Self-motion, steering, and obstacle avoidance during navigation in the real world require humans to travel along curved paths. Many perceptual models have been proposed that focus on heading, which specifies the direction of travel along straight paths, but not on path curvature, which humans accurately perceive and is critical to everyday locomotion. In primates, including humans, dorsal medial superior temporal area (MSTd) has been implicated in heading perception. However, the majority of MSTd neurons respond optimally to spiral patterns, rather than to the radial expansion patterns associated with heading. No existing theory of curved path perception explains the neural mechanisms by which humans accurately assess path and no functional role for spiral-tuned cells has yet been proposed. Here we present a computational model that demonstrates how the continuum of observed cells (radial to circular) in MSTd can simultaneously code curvature and heading across the neural population. Curvature is encoded through the spirality of the most active cell, and heading is encoded through the visuotopic location of the center of the most active cell's receptive field. Model curvature and heading errors fit those made by humans. Our model challenges the view that the function of MSTd is heading estimation, based on our analysis we claim that it is primarily concerned with trajectory estimation and the simultaneous representation of both curvature and heading. In our model, temporal dynamics afford time-history in the neural representation of optic flow, which may modulate its structure. This has far-reaching implications for the interpretation of studies that assume that optic flow is, and should be, represented as an instantaneous vector field. Our results suggest that spiral motion patterns that emerge in spatio-temporal optic flow are essential for guiding self-motion along complex trajectories, and that cells in MSTd are specifically tuned to extract complex trajectory

  17. Individual differences in behavioral and cardiovascular reactivity to emotive stimuli and their relationship to cognitive flexibility in a primate model of trait anxiety

    PubMed Central

    Shiba, Yoshiro; Santangelo, Andrea M.; Braesicke, Katrin; Agustín-Pavón, Carmen; Cockcroft, Gemma; Haggard, Mark; Roberts, Angela C.

    2014-01-01

    High trait anxiety is a risk factor for the development of anxiety disorders. Like the disorders themselves high trait anxiety has marked phenotypic variation at the level of symptomatology and neural circuits, suggesting that there may be different symptoms and distinct neural circuits associated with risk for these disorders. To address these issues, it is essential to develop reliable animal models of trait anxiety in a non-human primate whose brain bears structural and functional similarity to humans. The present study investigated individual variation in responsivity to fearful and anxiety provoking stimuli in the common marmoset monkey. Seven out of 27 animals failed to display discriminative, conditioned cardiovascular and behavioral responses on an auditory fear discrimination task, similar to that seen in high anxious humans and rodents. Their heightened emotionality to a rubber snake was consistent with the hypothesis that they were high in trait-like anxiety. Evidence for phenotypic variation in the high anxiety group was provided by the finding that discrimination failure was predicted early in conditioning by either hyper-vigilant scanning to the cues or a reduction in blood pressure to the context, i.e., test apparatus. Given that high trait anxiety in humans can be associated with altered prefrontal cognitive functioning and previously we implicated the marmoset anterior orbitofrontal (antOFC) and ventrolateral prefrontal cortex (vlPFC) in negative emotion regulation, we also tested the marmosets on two tests of cognitive flexibility differentially dependent on these two regions. While the high anxious group did not differ overall in their perseverative performance, the two distinct phenotypes were differentially correlated with reduced perseverative responding on the OFC- and vlPFC-dependent flexibility tests. Together, this study provides a new model of trait anxiety in marmosets amenable to analysis of phenotypic variation and neural circuitry

  18. Fetal signaling through placental structure and endocrine function: illustrations and implications from a nonhuman primate model.

    PubMed

    Rutherford, Julienne N

    2009-01-01

    The placenta is a transmitter of fetal need and fetal quality, interfacing directly with maternal physiology and ecology. Plasticity of placental structure and function across the developmental timeframe of gestation may serve as an important tool by which a fetus calibrates its growth to shifting maternal ecology and resource availability, and thereby signals its quality and adaptability to a changing environment. Signals of this quality may be conveyed by the size of the placental interface, an important marker of fetal access to maternal resources, or by production of placental insulin-like growth factor-II, a driver of fetoplacental growth. Litter size variation in the common marmoset monkey offers the opportunity to explore intrauterine resource allocation and placental plasticity in an important nonhuman primate model. Triplet marmosets are born at lower birth weights and have poorer postnatal outcomes and survivorship than do twins; triplet placentas differ in placental efficiency, microscopic morphology, and endocrine function. Through placental plasticity, triplet fetuses are able to adjust functional access to maternal resources in a way that allows pregnancy to proceed. However, the costs of such mechanisms may relate to reduced fetal growth and altered postnatal outcomes, with the potential to lead to adverse adult health consequences, suggesting an important link between the placenta itself and the developmental origins of health and disease.

  19. Environmental modulation of drug taking: Nonhuman primate models of cocaine abuse and PET neuroimaging.

    PubMed

    Nader, Michael A; Banks, Matthew L

    2014-01-01

    The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables - both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

  20. Primates in Human-Modified and Fragmented Landscapes: The Conservation Relevance of Modelling Habitat and Disturbance Factors in Density Estimation.

    PubMed

    Cavada, Nathalie; Barelli, Claudia; Ciolli, Marco; Rovero, Francesco

    2016-01-01

    Accurate density estimations of threatened animal populations is essential for management and conservation. This is particularly critical for species living in patchy and altered landscapes, as is the case for most tropical forest primates. In this study, we used a hierarchical modelling approach that incorporates the effect of environmental covariates on both the detection (i.e. observation) and the state (i.e. abundance) processes of distance sampling. We applied this method to already published data on three arboreal primates of the Udzungwa Mountains of Tanzania, including the endangered and endemic Udzungwa red colobus (Procolobus gordonorum). The area is a primate hotspot at continental level. Compared to previous, 'canonical' density estimates, we found that the inclusion of covariates in the modelling makes the inference process more informative, as it takes in full account the contrasting habitat and protection levels among forest blocks. The correction of density estimates for imperfect detection was especially critical where animal detectability was low. Relative to our approach, density was underestimated by the canonical distance sampling, particularly in the less protected forest. Group size had an effect on detectability, determining how the observation process varies depending on the socio-ecology of the target species. Lastly, as the inference on density is spatially-explicit to the scale of the covariates used in the modelling, we could confirm that primate densities are highest in low-to-mid elevations, where human disturbance tend to be greater, indicating a considerable resilience by target monkeys in disturbed habitats. However, the marked trend of lower densities in unprotected forests urgently calls for effective forest protection.

  1. The neural representation of the gender of faces in the primate visual system: A computer modeling study.

    PubMed

    Minot, Thomas; Dury, Hannah L; Eguchi, Akihiro; Humphreys, Glyn W; Stringer, Simon M

    2017-03-01

    We use an established neural network model of the primate visual system to show how neurons might learn to encode the gender of faces. The model consists of a hierarchy of 4 competitive neuronal layers with associatively modifiable feedforward synaptic connections between successive layers. During training, the network was presented with many realistic images of male and female faces, during which the synaptic connections are modified using biologically plausible local associative learning rules. After training, we found that different subsets of output neurons have learned to respond exclusively to either male or female faces. With the inclusion of short range excitation within each neuronal layer to implement a self-organizing map architecture, neurons representing either male or female faces were clustered together in the output layer. This learning process is entirely unsupervised, as the gender of the face images is not explicitly labeled and provided to the network as a supervisory training signal. These simulations are extended to training the network on rotating faces. It is found that by using a trace learning rule incorporating a temporal memory trace of recent neuronal activity, neurons responding selectively to either male or female faces were also able to learn to respond invariantly over different views of the faces. This kind of trace learning has been previously shown to operate within the primate visual system by neurophysiological and psychophysical studies. The computer simulations described here predict that similar neurons encoding the gender of faces will be present within the primate visual system. (PsycINFO Database Record

  2. A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management.

    PubMed

    Farese, Ann M; Cohen, Melanie V; Katz, Barry P; Smith, Cassandra P; Jackson, William; Cohen, Daniel M; MacVittie, Thomas J

    2012-10-01

    The development of medical countermeasures against the hematopoietic subsyndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to morbidity and mortality. Herein, the authors define these parameters for a nonhuman primate exposed to total body radiation and administered medical management. A blinded, randomized study (n = 48 rhesus macaques) determined the lethal dose-response relationship using bilateral 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90 Gy at 0.80 Gy min(-1). Following irradiation, animals were monitored for complete bloodcounts, body weight, temperature, diarrhea, and hydration status for 60 d. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics, and nutrition. The primary endpoint was survival at 60 d post-irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents, and tissue histology. The study defined an LD30/60 of 7.06 Gy, LD50/60 of 7.52 Gy, and an LD70/60 of 7.99 Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule.

  3. A Nonhuman Primate Model of the Hematopoietic Acute Radiation Syndrome Plus Medical Management

    PubMed Central

    Farese, A.M.; Cohen, M.V.; Katz, B. P.; Smith, C. P.; Jackson, W.; Cohen, D. M.; MacVittie, T.J.

    2012-01-01

    The development of medical countermeasures against the hematopoietic sub-syndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to the morbidity and mortality. Herein, we define these parameters for the nonhuman primate exposed to total-body radiation and administered medical management. A blinded, randomized study (n=48 rhesus macaques) determined the lethal dose response relationship using bilateral, 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90Gy at 0.80Gy minute−1. Following irradiation animals were monitored for complete blood counts, body weight, temperature, diarrhea, and hydration status for 60 days. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics and nutrition. The primary endpoint was survival at 60 days post irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents and tissue histology. The study defined an LD30/60 of 7.06Gy, LD50/60 of 7.52Gy, and an LD70/60 of 7.99Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule. PMID:22929469

  4. Biodistribution of Yttrium-90-Labeled Anti-CD45 Antibody in a Nonhuman Primate Model

    SciTech Connect

    Nemecek, Eneida; Hamlin, Donald K.; Fisher, Darrell R.; Krohn, Kenneth A.; Pagel, John M.; Applebaum, F. R.; Press, Oliver W.; Matthews, Dana C.

    2005-01-15

    Radioimmunotherapy may improve the outcome of hematopoietic cell transplantation for hematologic malignancies by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the organ localization of yttrium-90-labeled anti-CD45 (90Y-anti-CD45) antibody in macaques, a model that had previously predicted iodine-131-labeled anti-CD-45 (131I-anti-CD45) antibody biodistribution in humans. Experimental Design: Twelve Macaca nemestrina primates received anti-CD45 antibody labeled with 1 to 2 mCi of 90Y followed by serial blood sampling and marrow and lymph node biopsies, and necropsy. The content of 90Y per gram of tissue was determined by liquid scintillation spectrometry. Time-activity curves were constructed using average isotope concentrations in each tissue at measured time points to yield the fractional residence time and estimate radiation absorbed doses for each organ per unit of administered activity. The biodistribution of 90Y-anti-CD45 antibody was then compared with that previously obtained with 131I-anti-CD45 antibody in macaques. Results: The spleen received 2,120, marrow 1,060, and lymph nodes 315 cGy/mCi of 90Y injected. The liver and lungs were the nontarget organs receiving the highest radiation absorbed doses (440 and 285 cGy/mCi, respectively). Ytrrium-90-labeled anti-CD45 antibody delivered 2.5- and 3.7-fold more radiation to marrow than to liver and lungs, respectively. The ratios previously observed with 131I-antiCD45 antibody were 2.5-and 2.2-fold more radiation to marrow than to liver and lungs, respectively. Conclusions: This study shows that 90Y-anti-CD45 antibody can deliver relatively selective radiation to hematopoietic tissues, with similar ratios of radiation delivered to target versus nontarget organs, as compared with the 131I immunoconjugate in the same animal model.

  5. Potent neutralizing anti-CD1d antibody reduces lung cytokine release in primate asthma model

    PubMed Central

    Nambiar, Jonathan; Clarke, Adam W; Shim, Doris; Mabon, David; Tian, Chen; Windloch, Karolina; Buhmann, Chris; Corazon, Beau; Lindgren, Matilda; Pollard, Matthew; Domagala, Teresa; Poulton, Lynn; Doyle, Anthony G

    2015-01-01

    CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical. PMID:25751125

  6. Potent neutralizing anti-CD1d antibody reduces lung cytokine release in primate asthma model.

    PubMed

    Nambiar, Jonathan; Clarke, Adam W; Shim, Doris; Mabon, David; Tian, Chen; Windloch, Karolina; Buhmann, Chris; Corazon, Beau; Lindgren, Matilda; Pollard, Matthew; Domagala, Teresa; Poulton, Lynn; Doyle, Anthony G

    2015-01-01

    CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical.

  7. Validating a Nonhuman Primate Model of Super-Selective Intraophthalmic Artery Chemotherapy: Comparing Ophthalmic Artery Diameters

    PubMed Central

    Ditta, Lauren C.; Choudhri, Asim F.; Tse, Brian C.; Landers, Mark M.; Haik, Barrett G.; Steinle, Jena J.; Williams, J. Scott; Wilson, Matthew W.

    2012-01-01

    Purpose. Superselective intraophthalmic artery chemotherapy (SSIOAC) is being used for treatment of retinoblastoma; however, the hemodynamic consequences and toxicities are not fully known. We developed a nonhuman primate (NHP) model of SSIOAC and reported our clinical observations. For validation, we compared ophthalmic artery (OA) diameters between NHPs and children (<6 years). Methods. Endovascular cannulation of the right OA was performed three times each in six adult male Rhesus macaques. Angiographic OA images were obtained and measured, and postmortem OAs were histologically sectioned and measured. Retrospectively, computed tomography (CT) and magnetic resonance (MR) angiography images of the head in children and adolescents (as an adult reference) were used to measure the OA luminal diameter at its origin. Results. The median angiographic diameter of treated NHP OA origins (n = 6) was 1.06 mm (range 0.94–1.56). Histologic measurements (8 of 12 NHP OAs) gave a median diameter of 1.09 mm (range 0.95–1.41). In 98 children (from 169 consecutive CT and MR angiography studies; median age 1.01 years, range 0.01–5.74), 186 OAs were measurable at the origin (median luminal diameter 1.28 mm, range 0.82–2.00; P = 0.16 for the angiographic NHP diameters versus pediatric cohort). Angiographic measurements of 34 OAs (of 20 consecutive studies of adolescents; median age 16.55 years, range 14.40–18.18) gave a median luminal diameter of 1.45 mm (origin, range 1.13–1.66; P < 0.0001, adolescent versus pediatric). Conclusions. Measurements of the OA luminal diameter at its origin were similar between our NHP and pediatric cohort, validating our NHP model for testing both the hemodynamic consequences and toxicities of SSIOAC. PMID:23111611

  8. Crop Damage by Primates: Quantifying the Key Parameters of Crop-Raiding Events

    PubMed Central

    Wallace, Graham E.; Hill, Catherine M.

    2012-01-01

    Human-wildlife conflict often arises from crop-raiding, and insights regarding which aspects of raiding events determine crop loss are essential when developing and evaluating deterrents. However, because accounts of crop-raiding behaviour are frequently indirect, these parameters are rarely quantified or explicitly linked to crop damage. Using systematic observations of the behaviour of non-human primates on farms in western Uganda, this research identifies number of individuals raiding and duration of raid as the primary parameters determining crop loss. Secondary factors include distance travelled onto farm, age composition of the raiding group, and whether raids are in series. Regression models accounted for greater proportions of variation in crop loss when increasingly crop and species specific. Parameter values varied across primate species, probably reflecting differences in raiding tactics or perceptions of risk, and thereby providing indices of how comfortable primates are on-farm. Median raiding-group sizes were markedly smaller than the typical sizes of social groups. The research suggests that key parameters of raiding events can be used to measure the behavioural impacts of deterrents to raiding. Furthermore, farmers will benefit most from methods that discourage raiding by multiple individuals, reduce the size of raiding groups, or decrease the amount of time primates are on-farm. This study demonstrates the importance of directly relating crop loss to the parameters of raiding events, using systematic observations of the behaviour of multiple primate species. PMID:23056378

  9. Development of a Novel Preclinical Model of Pneumococcal Pneumonia in Nonhuman Primates

    PubMed Central

    Piantadosi, Claude A.; Benjamin, Ashlee M.; Lucas, Joseph E.; Zaas, Aimee K.; Betancourt-Quiroz, Marisol; Woods, Christopher W.; Chang, Alan L.; Roggli, Victor L.; Marshall, Craig D.; Ginsburg, Geoffrey S.; Welty-Wolf, Karen

    2014-01-01

    Pneumococcal pneumonia is a leading cause of bacterial infection and death worldwide. Current diagnostic tests for detecting Streptococcus pneumoniae can be unreliable and can mislead clinical decision-making and treatment. To address this concern, we developed a preclinical model of pneumococcal pneumonia in nonhuman primates useful for identifying novel biomarkers, diagnostic tests, and therapies for human S. pneumoniae infection. Adult colony-bred baboons (n = 15) were infected with escalating doses of S. pneumoniae (Serotype 19A-7). We characterized the pathophysiological and serological profiles of healthy and infected animals over 7 days. Pneumonia was prospectively defined by the presence of three criteria: (1) change in white blood cell count, (2) isolation of S. pneumoniae from bronchoalveolar lavage fluid (BALF) or blood, and (3) concurrent signs/symptoms of infection. Animals given 109 CFU consistently met our definition and developed a phenotype of tachypnea, tachycardia, fever, hypoxemia, and radiographic lobar infiltrates at 48 hours. BALF and plasma cytokines, including granulocyte colony-stimulating factor, IL-6, IL-10, and IL-1ra, peaked at 24 to 48 hours. At necropsy, there was lobar consolidation with frequent pleural involvement. Lung histopathology showed alveolar edema and macrophage influx in areas of organizing pneumonia. Hierarchical clustering of peripheral blood RNA data at 48 hours correctly identified animals with and without pneumonia. Dose-dependent inoculation of baboons with S. pneumoniae produces a host response ranging from spontaneous clearance (106 CFU) to severe pneumonia (109 CFU). Selected BALF and plasma cytokine levels and RNA profiles were associated with severe pneumonia and may provide clinically useful parameters after validation. PMID:24328793

  10. Metabolic response to high-carbohydrate and low-carbohydrate meals in a nonhuman primate model

    PubMed Central

    Fabbrini, Elisa; Higgins, Paul B.; Magkos, Faidon; Bastarrachea, Raul A.; Voruganti, V. Saroja; Comuzzie, Anthony G.; Shade, Robert E.; Gastaldelli, Amalia; Horton, Jay D.; Omodei, Daniela; Patterson, Bruce W.

    2013-01-01

    We established a model of chronic portal vein catheterization in an awake nonhuman primate to provide a comprehensive evaluation of the metabolic response to low-carbohydrate/high-fat (LCHF; 20% carbohydrate and 65% fat) and high-carbohydrate/low-fat (HCLF; 65% carbohydrate and 20% fat) meal ingestion. Each meal was given 1 wk apart to five young adult (7.8 ± 1.3 yr old) male baboons. A [U-13C]glucose tracer was added to the meal, and a [6,6-2H2]glucose tracer was infused systemically to assess glucose kinetics. Plasma areas under the curve (AUCs) of glucose, insulin, and C-peptide in the femoral artery and of glucose and insulin in the portal vein were higher (P ≤ 0.05) after ingestion of the HCLF compared with the LCHF meal. Compared with the LCHF meal, the rate of appearance of ingested glucose into the portal vein and the systemic circulation was greater after the HCLF meal (P < 0.05). Endogenous glucose production decreased by ∼40% after ingestion of the HCLF meal but was not affected by the LCHF meal (P < 0.05). Portal vein blood flow increased (P < 0.001) to a similar extent after consumption of either meal. In conclusion, a LCHF diet causes minimal changes in the rate of glucose appearance in both portal and systemic circulations, does not affect the rate of endogenous glucose production, and causes minimal stimulation of C-peptide and insulin. These observations demonstrate that LCHF diets cause minimal perturbations in glucose homeostasis and pancreatic β-cell activity. PMID:23269412

  11. Primate-Specific Regulation of Natural Killer Cells

    PubMed Central

    Parham, Peter; Abi-Rached, Laurent; Matevosyan, Lilit; Moesta, Achim K.; Norman, Paul J.; Aguilar, Anastazia M. Older; Guethlein, Lisbeth A.

    2010-01-01

    Summary Natural killer (NK) cells are circulating lymphocytes that function in innate immunity and placental reproduction. Regulating both development and function of NK cells is an array of variable and conserved receptors that interact with major histocompatibility complex (MHC) class I molecules. Families of lectin-like and immunoglobulin-like receptors are determined by genes in the natural killer (NKC) and leukocyte receptor (LRC) complexes, respectively. As a consequence of the strong, varying pressures on the immune and reproductive systems, NK cell receptors and their MHC class I ligands evolve rapidly, are highly diverse, and exhibit dramatic species-specific differences. The variable, polymorphic family of killer cell immunoglobulin-like receptors (KIR) that regulate human NK cell development and function evolved recently, from a single-copy gene during the evolution of simian primates. Our studies of KIR and MHC class I genes in representative species show how these two unlinked but functionally intertwined genetic complexes have co-evolved. In humans, combinations of KIR and HLA class I factors are associated with infectious diseases, including HIV/AIDS, autoimmunity, reproductive success and the outcome of therapeutic transplantation. The extraordinary, and unanticipated, divergence of human NK cell receptors and MHC class I ligands from their mouse counterparts can in part explain the difficulties experienced in finding informative mouse models for human diseases. Non-human primate models have far greater potential, but to realize their promise will first require more complete definition of the genetics and function of KIR and MHC variation in non-human primate species, at a level comparable to that achieved for the human species. PMID:20618586

  12. Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates.

    PubMed

    McAdams, Ryan M; McPherson, Ronald J; Kapur, Raj P; Juul, Sandra E

    2017-03-25

    Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O2 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated

  13. Comparison of ICRP 67 and Other Plutonium Systemic Model Predictions with the Biokinetic Data from Nonhuman Primates.

    PubMed

    Poudel, Deepesh; Krage, Eric Stephen; Brey, Richard Ray; Guilmette, Raymond A

    2016-04-01

    Despite the presence of a relatively large amount of human data available on the metabolism of plutonium, the experimental animal data is still important in constructing and parameterizing the biokinetic models. Recognizing this importance, the biokinetic data obtained from studies done by P.W. Durbin in nonhuman primates (NHP) were evaluated against the ICRP 67 systemic model and the two human models developed thereafter. The default transfer rates recommended for adult humans in these models predict the urinary excretion in NHP to a certain extent. However, they were unable to describe the fecal excretion rates several days post intake and the activities in skeleton and liver at the time of the death. These inconsistencies between the human reference models and the NHP biokinetic data are the result of metabolic and physiological differences between the species, as demonstrated by early biokinetic studies.

  14. The biological clock of very premature primate infants is responsive to light

    PubMed Central

    Hao, Haiping; Rivkees, Scott A.

    1999-01-01

    Each year more than 250,000 infants in the United States are exposed to artificial lighting in hospital nurseries with little consideration given to environmental lighting cycles. Essential in determining whether environmental lighting cycles need to be considered in hospital nurseries is identifying when the infant’s endogenous circadian clock becomes responsive to light. Using a non-human primate model of the developing human, we examined when the circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), becomes responsive to light. Preterm infant baboons of different ages were exposed to light (5,000 lux) at night, and then changes in SCN metabolic activity and gene expression were assessed. After exposure to bright light at night, robust increases in SCN metabolic activity and gene expression were seen at ages that were equivalent to human infants at 24 weeks after conception. These data provide direct evidence that the biological clock of very premature primate infants is responsive to light. PMID:10051658

  15. Captivity humanizes the primate microbiome

    PubMed Central

    Vangay, Pajau; Huang, Hu; Ward, Tonya; Hillmann, Benjamin M.; Al-Ghalith, Gabriel A.; Travis, Dominic A.; Long, Ha Thang; Tuan, Bui Van; Minh, Vo Van; Cabana, Francis; Nadler, Tilo; Toddes, Barbara; Murphy, Tami; Glander, Kenneth E.; Johnson, Timothy J.; Knights, Dan

    2016-01-01

    The primate gastrointestinal tract is home to trillions of bacteria, whose composition is associated with numerous metabolic, autoimmune, and infectious human diseases. Although there is increasing evidence that modern and Westernized societies are associated with dramatic loss of natural human gut microbiome diversity, the causes and consequences of such loss are challenging to study. Here we use nonhuman primates (NHPs) as a model system for studying the effects of emigration and lifestyle disruption on the human gut microbiome. Using 16S rRNA gene sequencing in two model NHP species, we show that although different primate species have distinctive signature microbiota in the wild, in captivity they lose their native microbes and become colonized with Prevotella and Bacteroides, the dominant genera in the modern human gut microbiome. We confirm that captive individuals from eight other NHP species in a different zoo show the same pattern of convergence, and that semicaptive primates housed in a sanctuary represent an intermediate microbiome state between wild and captive. Using deep shotgun sequencing, chemical dietary analysis, and chloroplast relative abundance, we show that decreasing dietary fiber and plant content are associated with the captive primate microbiome. Finally, in a meta-analysis including published human data, we show that captivity has a parallel effect on the NHP gut microbiome to that of Westernization in humans. These results demonstrate that captivity and lifestyle disruption cause primates to lose native microbiota and converge along an axis toward the modern human microbiome. PMID:27573830

  16. The fourth dimension of tool use: temporally enduring artefacts aid primates learning to use tools.

    PubMed

    Fragaszy, D M; Biro, D; Eshchar, Y; Humle, T; Izar, P; Resende, B; Visalberghi, E

    2013-11-19

    All investigated cases of habitual tool use in wild chimpanzees and capuchin monkeys include youngsters encountering durable artefacts, most often in a supportive social context. We propose that enduring artefacts associated with tool use, such as previously used tools, partly processed food items and residual material from previous activity, aid non-human primates to learn to use tools, and to develop expertise in their use, thus contributing to traditional technologies in non-humans. Therefore, social contributions to tool use can be considered as situated in the three dimensions of Euclidean space, and in the fourth dimension of time. This notion expands the contribution of social context to learning a skill beyond the immediate presence of a model nearby. We provide examples supporting this hypothesis from wild bearded capuchin monkeys and chimpanzees, and suggest avenues for future research.

  17. The fourth dimension of tool use: temporally enduring artefacts aid primates learning to use tools

    PubMed Central

    Fragaszy, D. M.; Biro, D.; Eshchar, Y.; Humle, T.; Izar, P.; Resende, B.; Visalberghi, E.

    2013-01-01

    All investigated cases of habitual tool use in wild chimpanzees and capuchin monkeys include youngsters encountering durable artefacts, most often in a supportive social context. We propose that enduring artefacts associated with tool use, such as previously used tools, partly processed food items and residual material from previous activity, aid non-human primates to learn to use tools, and to develop expertise in their use, thus contributing to traditional technologies in non-humans. Therefore, social contributions to tool use can be considered as situated in the three dimensions of Euclidean space, and in the fourth dimension of time. This notion expands the contribution of social context to learning a skill beyond the immediate presence of a model nearby. We provide examples supporting this hypothesis from wild bearded capuchin monkeys and chimpanzees, and suggest avenues for future research. PMID:24101621

  18. Transgenerational effects of binge drinking in a primate model: implications for human health

    PubMed Central

    VandeVoort, Catherine A.; Grimsrud, Kristin N.; Midic, Uros; Mtango, Namdori; Latham, Keith E.

    2014-01-01

    Objective To determine if binge ethanol prior to ovulation affects oocyte quality and gene expression and subsequent embryo development Design Binge ethanol given twice weekly for 6 months followed by standard IVF cycle and subsequent natural mating. Setting Research University – National Primate Research Center Animals Adult female rhesus monkeys Interventions Binge ethanol twice weekly for 6 months prior to standard in vitro fertilization cycle with or without embryo culture. With in vivo development, ethanol treatment continued until pregnancy was identified. Main Outcome Measures Oocyte and cumulus/granulosa cell gene expression, embryo development to blastocyst and pregnancy rate Results Reduced embryo development in vitro, changes in oocyte and cumulus cell gene expression, and an increase in spontaneous abortion during very early gestation Conclusions This study provides evidence that binge drinking can affect the developmental potential of oocytes even after alcohol consumption had ceased. PMID:25492684

  19. The Development of Hand-Centered Visual Representations in the Primate Brain: A Computer Modeling Study Using Natural Visual Scenes

    PubMed Central

    Galeazzi, Juan M.; Minini, Loredana; Stringer, Simon M.

    2015-01-01

    Neurons that respond to visual targets in a hand-centered frame of reference have been found within various areas of the primate brain. We investigate how hand-centered visual representations may develop in a neural network model of the primate visual system called VisNet, when the model is trained on images of the hand seen against natural visual scenes. The simulations show how such neurons may develop through a biologically plausible process of unsupervised competitive learning and self-organization. In an advance on our previous work, the visual scenes consisted of multiple targets presented simultaneously with respect to the hand. Three experiments are presented. First, VisNet was trained with computerized images consisting of a realistic image of a hand and a variety of natural objects, presented in different textured backgrounds during training. The network was then tested with just one textured object near the hand in order to verify if the output cells were capable of building hand-centered representations with a single localized receptive field. We explain the underlying principles of the statistical decoupling that allows the output cells of the network to develop single localized receptive fields even when the network is trained with multiple objects. In a second simulation we examined how some of the cells with hand-centered receptive fields decreased their shape selectivity and started responding to a localized region of hand-centered space as the number of objects presented in overlapping locations during training increases. Lastly, we explored the same learning principles training the network with natural visual scenes collected by volunteers. These results provide an important step in showing how single, localized, hand-centered receptive fields could emerge under more ecologically realistic visual training conditions. PMID:26696876

  20. Novel Primate Model of Serotonin Transporter Genetic Polymorphisms Associated with Gene Expression, Anxiety and Sensitivity to Antidepressants

    PubMed Central

    Santangelo, Andrea M; Ito, Mitsuteru; Shiba, Yoshiro; Clarke, Hannah F; Schut, Evelien HS; Cockcroft, Gemma; Ferguson-Smith, Anne C; Roberts, Angela C

    2016-01-01

    Genetic polymorphisms in the repeat upstream region of the serotonin transporter gene (SLC6A4) are associated with individual differences in stress reactivity, vulnerability to affective disorders, and response to pharmacotherapy. However, the molecular, neurodevelopmental and psychopharmacological mechanisms underlying the link between SLC6A4 polymorphisms and the emotionally vulnerable phenotype are not fully understood. Thus, using the marmoset monkey Callithrix jacchus we characterize here a new neurobiological model to help to address these questions. We first sequenced the marmoset SLC6A4 promoter and identified a double nucleotide polymorphism (−2053AC/CT) and two single-nucleotide polymorphisms (−2022C/T and −1592G/C) within the repeat upstream region. We showed their association with gene expression using in vivo quantitative PCR and with affective behavior using a primate test of anxiety (human intruder test). The low-expressing haplotype (AC/C/G) was linked with high anxiety while the high-expressing one (CT/T/C) was associated with an active coping strategy in response to threat. Pharmacological challenge with an acute dose of the selective serotonin reuptake inhibitor, citalopram, revealed a genotype-dependent behavioral response. While individuals homozygous for the high anxiety-related haplotype AC/C/G exhibited a dose-dependent, anxiogenic response, individuals homozygous for the low anxiety-related haplotype CT/T/C showed an opposing, dose-dependent anxiolytic effect. These findings provide a novel genetic and behavioral primate model to study the molecular, neurodevelopmental, and psychopharmacological mechanisms that underlie genetic variation-associated complex behaviors, with specific implications for the understanding of normal and abnormal serotonin actions and the development of personalized pharmacological treatments for psychiatric disorders. PMID:26997299

  1. Biology of primate relaxin: A paracrine signal in early pregnancy?

    PubMed Central

    Hayes, Eric S

    2004-01-01

    Relaxin is a peptide hormone that exerts numerous effects in a variety of tissues across a broad range of species. Although first identified more than 75 years ago interest in relaxin biology has waxed and waned over the years consistent with peaks and troughs of new experimental data on its wide-ranging biological effects and advances in relaxin enabling technologies. Recent insights into species-dependent differences in relaxin biology during pregnancy have once again stimulated a relative surge of interest in the study of relaxin's reproductive biology. Identification and pharmacological characterization of orphaned relaxin receptors and exploration of its paracrine effects on pregnancy using genomic and proteomic technologies have succeeded in fueling current interest in relaxin research. Primates and non-primate vertebrates exhibit very disparate profiles of relaxin genomics, proteomics and functional biology. Non-human primates appear to exhibit a very close similarity to humans with respect to relaxin reproductive biology but the similarities and subtle differences are only just beginning to be understood. We, and others, have shown that relaxin produces significant changes to the non-human primate endometrium during the peri-implantation period that are consistent with relaxin's long perceived role as a paracrine modulator of pregnancy. The purpose of this review is to summarize the reproductive biology of relaxin in non-human primates with a specific emphasis on the paracrine role of ovarian and endometrial relaxin during embryo implantation and early pregnancy. PMID:15200675

  2. Using viral-mediated gene delivery to model Parkinson's disease: do nonhuman primate investigations expand our understanding?

    PubMed

    Fiandaca, Massimo S; Federoff, Howard J

    2014-06-01

    In this review, we consider the use of nonhuman primate (NHP) models of Parkinson's disease (PD) produced using viral-mediated gene delivery and information they provide in comparison to other model systems in rodents and NHPs. To date, rodent and NHP PD models have found it difficult to fully recapitulate the human disorder and, therefore, provide little actual insight into disease progression. The viral-mediated gene delivery method for α-synuclein has been shown to produce a parkinsonian rodent and NHP. This novel viral-mediated gene transfer model in the NHP appears to provide a significant advance beyond neurotoxicant models, by more closely mimicking the more chronic time course of developed behavioral deterioration and neuropathology. Although we agree that the use of these novel methods inducing parkinsonian NHPs may provide relevant treatment insights, beyond those of more standard PD models, we remain cautious as to the preclinical models' ability to predict outcomes in human trials. In specific cases of certain novel medical therapeutics, therefore, we also consider the phase 0 clinical trial as offering an alternative to the currently non-predictive preclinical models, including those in the NHP.

  3. Identifying constraints in the evolution of primate societies.

    PubMed

    Thierry, Bernard

    2013-05-19

    The evolutionary study of social systems in non-human primates has long been focused on ecological determinants. The predictive value of socio-ecological models remains quite low, however, in particular because such equilibrium models cannot integrate the course of history. The use of phylogenetic methods indicates that many patterns of primate societies have been conserved throughout evolutionary history. For example, the study of social relations in macaques revealed that their social systems are made of sets of correlated behavioural traits. Some macaque species are portrayed by marked social intolerance, a steep dominance gradient and strong nepotism, whereas others display a higher level of social tolerance, relaxed dominance and a weaker influence of kinship. Linkages between behavioural traits occur at different levels of organization, and act as constraints that limit evolutionary responses to external pressures. Whereas these constraints can exert strong stabilizing selection that opposes the potential changes required by the ecological environment, selective mechanisms may have the potential to switch the whole social system from one state to another by acting primarily on some key behavioural traits that could work as pacemakers.

  4. A bovine model for polycystic ovary syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polycystic ovary syndrome (PCOS) results in the greatest single cause of anovulatory infertility in reproductive age women (affecting 5-10%). Previously, research groups have created animal models utilizing non-human primates and sheep to better understand the mechanisms involved in PCOS. However, c...

  5. Relevance of animal models to human tardive dyskinesia

    PubMed Central

    2012-01-01

    Tardive dyskinesia remains an elusive and significant clinical entity that can possibly be understood via experimentation with animal models. We conducted a literature review on tardive dyskinesia modeling. Subchronic antipsychotic drug exposure is a standard approach to model tardive dyskinesia in rodents. Vacuous chewing movements constitute the most common pattern of expression of purposeless oral movements and represent an impermanent response, with individual and strain susceptibility differences. Transgenic mice are also used to address the contribution of adaptive and maladaptive signals induced during antipsychotic drug exposure. An emphasis on non-human primate modeling is proposed, and past experimental observations reviewed in various monkey species. Rodent and primate models are complementary, but the non-human primate model appears more convincingly similar to the human condition and better suited to address therapeutic issues against tardive dyskinesia. PMID:22404856