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Sample records for non-human primate exposed

  1. Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation.

    PubMed

    Selemon, L D; Friedman, H R

    2013-09-17

    A number of psychiatric illnesses have been associated with prenatal disturbance of brain development, including autism, attention deficit hyperactivity disorder, and schizophrenia. Individuals afflicted with these disorders exhibit both repetitive motor and cognitive behavior. The potential role that environmental insult to the developing brain may play in generating these aberrant behaviors is unclear. Here we examine the behavioral consequences of an early gestational insult in the non-human primate. Rhesus macaques were exposed to x-irradiation during the first trimester of development to disrupt neurogenesis. The behavior of five fetally irradiated monkeys (FIMs) and five control monkeys (CONs) was observed as they matured from juvenile (1.5 years) to adult ages (4-5 years). Home-cage behavior was indistinguishable in the two groups. In the testing cage, circling was prevalent in both groups at juvenile ages, persisting to adulthood in three of the five FIMs. One FIM executed a ritualized motor sequence marked by semi-circling and undulating head movements. Seven macaques (4 FIMs, 3 CONs) were tested on a spatial Delayed Alternation (DA) task as adults. Perseverative errors and non-perseverative errors were recorded in early stages of the testing, at the 0 delay interval. While performing DA, FIMs made more errors of perseveration than CONs yet the number of total errors committed did not differ between groups. The presence of motor stereotypies and cognitive perseveration in fetally irradiated non-human primates suggests that environmental insult to the embryonic brain may contribute to repetitive motor and cognitive behaviors in neuropsychiatric diseases. PMID:23769911

  2. [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. PMID:23389980

  3. Impaired control of body cooling during heterothermia represents the major energetic constraint in an aging non-human primate exposed to cold.

    PubMed

    Terrien, Jeremy; Zahariev, Alexandre; Blanc, Stephane; Aujard, Fabienne

    2009-01-01

    Daily heterothermia is used by small mammals for energy and water savings, and seems to be preferentially exhibited during winter rather than during summer. This feature induces a trade-off between the energy saved during daily heterothermia and the energy cost of arousal, which can impact energy balance and survival under harsh environmental conditions. Especially, aging may significantly affect such trade off during cold-induced energy stress, but direct evidences are still lacking. We hypothesized that aging could alter the energetics of daily heterothermia, and that the effects could differ according to season. In the gray mouse lemur (Microcebus murinus), a non-human primate species which exhibits daily heterothermia, we investigated the effects of exposures to 25 and 12 degrees C on body composition, energy balance, patterns of heterothermia and water turnover in adult (N = 8) and aged animals (N = 7) acclimated to winter-like or summer-like photoperiods. Acclimation to summer prevented animals from deep heterothermia, even during aging. During winter, adult animals at 12 degrees C and aged animals at 25 degrees C exhibited low levels of energy expenditure with minor modulations of heterothermia. The major effects of cold were observed during winter, and were particularly pronounced in aged mouse lemurs which exhibited deep heterothermia phases. Body composition was not significantly affected by age and could not explain the age-related differences in heterothermia patterns. However, aging was associated with increased levels of energy expenditure during cold exposure, in concomitance with impaired energy balance. Interestingly, increased energy expenditure and depth of heterothermia phases were strongly correlated. In conclusion, it appeared that the exhibition of shallow heterothermia allowed energy savings during winter in adult animals only. Aged animals exhibited deep heterothermia and increased levels of energy expenditure, impairing energy balance

  4. 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

  5. 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. PMID:24038444

  6. 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

  7. 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

  8. Nepotistic cooperation in non-human primate groups

    PubMed Central

    Silk, Joan B.

    2009-01-01

    Darwin was struck by the many similarities between humans and other primates and believed that these similarities were the product of common ancestry. He would be even more impressed by the similarities if he had known what we have learned about primates over the last 50 years. Genetic kinship has emerged as the primary organizing force in the evolution of primate social organization and the patterning of social behaviour in non-human primate groups. There are pronounced nepotistic biases across the primate order, from tiny grey mouse lemurs (Microcebus murinus) that forage alone at night but cluster with relatives to sleep during the day, to cooperatively breeding marmosets that rely on closely related helpers to rear their young, rhesus macaque (Macaca mulatta) females who acquire their mother's rank and form strict matrilineal dominance hierarchies, male howler monkeys that help their sons maintain access to groups of females and male chimpanzees (Pan troglodytes) that form lasting relationships with their brothers. As more evidence of nepotism has accumulated, important questions about the evolutionary processes underlying these kin biases have been raised. Although kin selection predicts that altruism will be biased in favour of relatives, it is difficult to assess whether primates actually conform to predictions derived from Hamilton's rule: br > c. In addition, other mechanisms, including contingent reciprocity and mutualism, could contribute to the nepotistic biases observed in non-human primate groups. There are good reasons to suspect that these processes may complement the effects of kin selection and amplify the extent of nepotistic biases in behaviour. PMID:19805431

  9. Nepotistic cooperation in non-human primate groups.

    PubMed

    Silk, Joan B

    2009-11-12

    Darwin was struck by the many similarities between humans and other primates and believed that these similarities were the product of common ancestry. He would be even more impressed by the similarities if he had known what we have learned about primates over the last 50 years. Genetic kinship has emerged as the primary organizing force in the evolution of primate social organization and the patterning of social behaviour in non-human primate groups. There are pronounced nepotistic biases across the primate order, from tiny grey mouse lemurs (Microcebus murinus) that forage alone at night but cluster with relatives to sleep during the day, to cooperatively breeding marmosets that rely on closely related helpers to rear their young, rhesus macaque (Macaca mulatta) females who acquire their mother's rank and form strict matrilineal dominance hierarchies, male howler monkeys that help their sons maintain access to groups of females and male chimpanzees (Pan troglodytes) that form lasting relationships with their brothers. As more evidence of nepotism has accumulated, important questions about the evolutionary processes underlying these kin biases have been raised. Although kin selection predicts that altruism will be biased in favour of relatives, it is difficult to assess whether primates actually conform to predictions derived from Hamilton's rule: br > c. In addition, other mechanisms, including contingent reciprocity and mutualism, could contribute to the nepotistic biases observed in non-human primate groups. There are good reasons to suspect that these processes may complement the effects of kin selection and amplify the extent of nepotistic biases in behaviour. PMID:19805431

  10. The origins of non-human primates' manual gestures

    PubMed Central

    Liebal, Katja; Call, Josep

    2012-01-01

    The increasing body of research into human and non-human primates' gestural communication reflects the interest in a comparative approach to human communication, particularly possible scenarios of language evolution. One of the central challenges of this field of research is to identify appropriate criteria to differentiate a gesture from other non-communicative actions. After an introduction to the criteria currently used to define non-human primates' gestures and an overview of ongoing research, we discuss different pathways of how manual actions are transformed into manual gestures in both phylogeny and ontogeny. Currently, the relationship between actions and gestures is not only investigated on a behavioural, but also on a neural level. Here, we focus on recent evidence concerning the differential laterality of manual actions and gestures in apes in the framework of a functional asymmetry of the brain for both hand use and language. PMID:22106431

  11. 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.

  12. Voice processing in human and non-human primates

    PubMed Central

    Belin, Pascal

    2006-01-01

    Humans share with non-human primates a number of voice perception abilities of crucial importance in social interactions, such as the ability to identify a conspecific individual from its vocalizations. Speech perception is likely to have evolved in our ancestors on the basis of pre-existing neural mechanisms involved in extracting behaviourally relevant information from conspecific vocalizations (CVs). Studying the neural bases of voice perception in primates thus not only has the potential to shed light on cerebral mechanisms that may be—unlike those involved in speech perception—directly homologous between species, but also has direct implications for our understanding of how speech appeared in humans. In this comparative review, we focus on behavioural and neurobiological evidence relative to two issues central to voice perception in human and non-human primates: (i) are CVs ‘special’, i.e. are they analysed using dedicated cerebral mechanisms not used for other sound categories, and (ii) to what extent and using what neural mechanisms do primates identify conspecific individuals from their vocalizations? PMID:17118926

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

    PubMed

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

    2015-05-22

    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

  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. 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…

  16. 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

  17. 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. PMID:24807743

  18. The distribution of pol containing human endogenous retroviruses in non-human primates.

    PubMed

    Greenwood, Alex D; Stengel, Anna; Erfle, Volker; Seifarth, Wolfgang; Leib-Mösch, Christine

    2005-04-10

    Few human endogenous retroviruses (HERVs) have been extensively studied in non-human primates. Such investigations have demonstrated that several element classes are primate unique, contain members with important biological function, are conserved in specific primate lineages, and have in some cases expanded in copy number. We have examined multiple sub-families of all major groups of HERVs using a DNA microarray based on the reverse transcriptase (RT) domain of the viral polymerase gene (pol). The microarray was used to investigate the distribution of HERVs in non-human primates with particular focus on the differences between New World monkeys (NWMs) and other anthropoids. This is the first study examining most HERV families in multiple non-human primate DNAs using a uniform and sensitive method and suggests that major differences exist between primate groups. The results indicate that a major invasion and expansion of pol containing HERVs occurred after the platyrrhine (NWM) lineage separated from the catarrhines (Old World Monkeys and apes). PMID:15780870

  19. Mean Organ Doses Resulting From Non-Human Primate Whole Thorax Lung Irradiation Prescribed to Mid-Line Tissue.

    PubMed

    Prado, Charlotte; Kazi, Abdul; Bennett, Alexander; MacVittie, Thomas; Prado, Karl

    2015-11-01

    Multi-organ dose evaluations and the effects of heterogeneous tissue dose calculations have been retrospectively evaluated following irradiation to the whole thorax and lung in non-human primates (NHP). A clinical-based approach was established to evaluate actual doses received in the heart and lungs during whole thorax lung irradiation. Anatomical structure and organ densities have been introduced in the calculations to show the effects of dose distribution through heterogeneous tissue. Mean organ doses received by non-human primates undergoing whole thorax lung irradiations were calculated using a treatment planning system that is routinely used in clinical radiation oncology. The doses received by non-human primates irradiated following conventional dose calculations have been retrospectively reconstructed using computerized tomography-based, heterogeneity-corrected dose calculations. The use of dose volume descriptors for irradiation to organs at risk and tissue exposed to radiation is introduced. Mean and partial-volume doses to lung and heart are presented and contrasted. The importance of exact dose definitions is highlighted, and the relevance of precise dosimetry to establish organ-specific dose response relationships in NHP models of acute and delayed effects of acute radiation exposure is emphasized. PMID:26425898

  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. Cryopreservation of non-human primate sperm: priorities for future research.

    PubMed

    Morrell, J M; Hodges, J K

    1998-10-01

    Wild populations of many non-human primate species have declined alarmingly due to habitat destruction, hunting and genetic isolation. Captive breeding programmes to aid species survival could be enhanced by the use of assisted reproductive techniques, such as artificial insemination (AI), if a source of viable sperm was readily accessible. Cryobanks of primate sperm could provide such a supply if techniques for freezing sperm could be developed. Although sporadic attempts to cryopreserve primate sperm have been reported for some of the more frequently encountered zoo-maintained species, there is limited information available on techniques for sperm collection and storage. It is vital that adequate reporting of all cryopreservation attempts be made to avoid repetition of inappropriate methodologies and wastage of valuable genetic material from rare or endangered animals. An integrated approach to the cryobanking of non-human primate sperm is considered to be essential for species conservation. In this review, the factors affecting the success of sperm cryopreservation are outlined, existing information is compiled from previous reported attempts at cryopreservation, and suggestions are made for cryopreserving sperm in further non-human primate species. Moreover, recommendations are given for additional studies to augment existing data. It is intended that this information should serve as a guide for developing cryopreservation protocols in the future, particularly for endangered species. PMID:9835366

  2. 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

  3. Reactivity of anti-glycophorin monoclonal antibodies (Mabs) in tests with red cells of non-human primates.

    PubMed

    Blancher, A; Socha, W W; Reid, M E

    1997-01-01

    Seventy Mabs against human glycophorins (GP) and band 3 were tested with red blood cells (RBCs) of various non-human primates, from anthropoid apes to monkeys. Differences among Mabs reactivity in tests with non-human primate RBCs reflect the complexity of the immune reactions to human GPs and provide insights into aspects of evolution and a tool to epitope map. PMID:9095507

  4. 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

  5. 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.

  6. 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. PMID:18692539

  7. Initial gene vector dosing for studying symptomatology of amyotrophic lateral sclerosis in non-human primates

    PubMed Central

    Jackson, Kasey L.; Dayton, Robert D.; Fisher-Perkins, Jeanne M.; Didier, Peter J.; Baker, Kate C.; Weimer, Maria; Gutierrez, Amparo; Cain, Cooper D.; Mathis, J. Michael; Gitcho, Michael A.; Bunnell, Bruce A.; Klein, Ronald L.

    2015-01-01

    Background Most amyotrophic lateral sclerosis (ALS) research has focused on mice, but there are distinct differences in the functional neuroanatomy of the corticospinal pathway in primates vs. rodents. A non-human primate model may be more sensitive and more predictive for therapeutic efficacy. Methods Rhesus macaques received recombinant adeno-associated virus (AAV9) encoding either the ALS-related pathological protein TDP-43 or a green fluorescent protein (GFP) control by intravenous administration. Motor function and electromyography were assessed over a nine-month expression interval followed by post-mortem analyses. Results Recombinant TDP-43 or GFP was stably expressed long term. Although the TDP-43 subjects did not manifest severe paralysis and atrophy, there were trends of a partial disease state in the TDP-43 subjects relative to the control. Conclusions These data indicate that a higher gene vector dose will likely be necessary for more robust effects, yet augur that a relevant primate model is feasible. PMID:25639184

  8. Primate drum kit: a system for studying acoustic pattern production by non-human primates using acceleration and strain sensors.

    PubMed

    Ravignani, Andrea; Matellán Olivera, Vicente; Gingras, Bruno; Hofer, Riccardo; Rodríguez Hernández, Carlos; 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

  9. 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

  10. 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

  11. 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. PMID:25714101

  12. Human and non-human primate genomes share hotspots of positive selection.

    PubMed

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

    2010-02-01

    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

  13. Phylogenetic Evidence That Two Distinct Trichuris Genotypes Infect both Humans and Non-Human Primates

    PubMed Central

    Ravasi, Damiana F.; O’Riain, Mannus J.; Davids, Faezah; Illing, Nicola

    2012-01-01

    Although there has been extensive debate about whether Trichuris suis and Trichuris trichiura are separate species, only one species of the whipworm T. trichiura has been considered to infect humans and non-human primates. In order to investigate potential cross infection of Trichuris sp. between baboons and humans in the Cape Peninsula, South Africa, we sequenced the ITS1-5.8S-ITS2 region of adult Trichuris sp. worms isolated from five baboons from three different troops, namely the Cape Peninsula troop, Groot Olifantsbos troop and Da Gama Park troop. This region was also sequenced from T. trichiura isolated from a human patient from central Africa (Cameroon) for comparison. By combining this dataset with Genbank records for Trichuris isolated from other humans, non-human primates and pigs from several different countries in Europe, Asia, and Africa, we confirmed the identification of two distinct Trichuris genotypes that infect primates. Trichuris sp. isolated from the Peninsula baboons fell into two distinct clades that were found to also infect human patients from Cameroon, Uganda and Jamaica (named the CP-GOB clade) and China, Thailand, the Czech Republic, and Uganda (named the DG clade), respectively. The divergence of these Trichuris clades is ancient and precedes the diversification of T. suis which clustered closely to the CP-GOB clade. The identification of two distinct Trichuris genotypes infecting both humans and non-human primates is important for the ongoing treatment of Trichuris which is estimated to infect 600 million people worldwide. Currently baboons in the Cape Peninsula, which visit urban areas, provide a constant risk of infection to local communities. A reduction in spatial overlap between humans and baboons is thus an important measure to reduce both cross-transmission and zoonoses of helminthes in Southern Africa. PMID:22952922

  14. 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. PMID:26046952

  15. Tissue-specific transcriptome sequencing analysis expands the non-human primate reference transcriptome resource (NHPRTR)

    PubMed Central

    Peng, Xinxia; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Nishida, Andrew; Pipes, Lenore; Bozinoski, Marjan; Thomas, Matthew J.; Kelly, Sara; Weiss, Jeffrey M.; Raveendran, Muthuswamy; Muzny, Donna; Gibbs, Richard A.; Rogers, Jeffrey; Schroth, Gary P.; Katze, Michael G.; Mason, Christopher E.

    2015-01-01

    The non-human primate reference transcriptome resource (NHPRTR, available online at http://nhprtr.org/) aims to generate comprehensive RNA-seq data from a wide variety of non-human primates (NHPs), from lemurs to hominids. In the 2012 Phase I of the NHPRTR project, 19 billion fragments or 3.8 terabases of transcriptome sequences were collected from pools of ∼20 tissues in 15 species and subspecies. Here we describe a major expansion of NHPRTR by adding 10.1 billion fragments of tissue-specific RNA-seq data. For this effort, we selected 11 of the original 15 NHP species and subspecies and constructed total RNA libraries for the same ∼15 tissues in each. The sequence quality is such that 88% of the reads align to human reference sequences, allowing us to compute the full list of expression abundance across all tissues for each species, using the reads mapped to human genes. This update also includes improved transcript annotations derived from RNA-seq data for rhesus and cynomolgus macaques, two of the most commonly used NHP models and additional RNA-seq data compiled from related projects. Together, these comprehensive reference transcriptomes from multiple primates serve as a valuable community resource for genome annotation, gene dynamics and comparative functional analysis. PMID:25392405

  16. 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

  17. 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. PMID:25465081

  18. 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

  19. The contribution of non-human primate models to the development of human vaccines.

    PubMed

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

    2014-12-01

    The non-human 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

  20. 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

  1. The Ethics of Using Transgenic Non-Human Primates to Study What Makes Us Human

    PubMed Central

    Coors, Marilyn E.; Glover, Jacqueline J.; Juengst, Eric T.; Sikela, James M.

    2010-01-01

    An ongoing flood of comparative genomic data is identifying human lineage specific (HLS) sequences of unknown function, and there is strong interest in investigating their functional effects. Transgenic apes, our closest evolutionary relative, have the highest potential to express HLS sequences as they are expressed in Homo sapiens and likewise experience harm from such transgenic research. These harms render the conduct of this research ethically unacceptable in apes, justifying regulatory barriers between these species and all other non-human primates for transgenic research. PMID:20717156

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

    PubMed

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

    2014-02-01

    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

  3. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates.

    PubMed

    Sullivan, Nancy J; Geisbert, Thomas W; Geisbert, Joan B; Xu, Ling; Yang, Zhi-Yong; Roederer, Mario; Koup, Richard A; Jahrling, Peter B; Nabel, Gary J

    2003-08-01

    Containment of highly lethal Ebola virus outbreaks poses a serious public health challenge. Although an experimental vaccine has successfully protected non-human primates against disease, more than six months was required to complete the immunizations, making it impractical to limit an acute epidemic. Here, we report the development of accelerated vaccination against Ebola virus in non-human primates. The antibody response to immunization with an adenoviral (ADV) vector encoding the Ebola glycoprotein (GP) was induced more rapidly than with DNA priming and ADV boosting, but it was of lower magnitude. To determine whether this earlier immune response could nonetheless protect against disease, cynomolgus macaques were challenged with Ebola virus after vaccination with ADV-GP and nucleoprotein (NP) vectors. Protection was highly effective and correlated with the generation of Ebola-specific CD8(+) T-cell and antibody responses. Even when animals were immunized once with ADV-GP/NP and challenged 28 days later, they remained resistant to challenge with either low or high doses of virus. This accelerated vaccine provides an intervention that may help to limit the epidemic spread of Ebola, and is applicable to other viruses. PMID:12904795

  4. Social isolation disrupts hippocampal neurogenesis in young non-human primates

    PubMed Central

    Cinini, Simone M.; Barnabe, Gabriela F.; Galvão-Coelho, Nicole; de Medeiros, Magda A.; Perez-Mendes, Patrícia; Sousa, Maria B. C.; Covolan, Luciene; Mello, Luiz E.

    2014-01-01

    Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for 1 or 3 weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming—an indicative of attenuation of tension—was reduced among isolated marmosets. These results were consistent with increased cortisol levels after 1 and 3 weeks of isolation. After social isolation (1 or 3 weeks), reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling). Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions. PMID:24733997

  5. Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models

    PubMed Central

    Tuero, Iskra; Robert-Guroff, Marjorie

    2014-01-01

    An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinical studies in non-human primate models have facilitated progress in mucosal vaccine development by evaluating candidate vaccine approaches, developing methodologies for collecting and assessing mucosal samples, and providing clues to immune correlates of protective immunity for further investigation. In this review we have focused on non-human primate studies which have provided important information for future design of vaccine strategies, targeting of mucosal inductive sites, and assessment of mucosal immunity. Knowledge gained in these studies will inform mucosal vaccine design and evaluation in human clinical trials. PMID:25196380

  6. Elevated gene expression levels distinguish human from non-human primate brains

    PubMed Central

    Cáceres, Mario; Lachuer, Joel; Zapala, Matthew A.; Redmond, John C.; Kudo, Lili; Geschwind, Daniel H.; Lockhart, David J.; Preuss, Todd M.; Barlow, Carrolee

    2003-01-01

    Little is known about how the human brain differs from that of our closest relatives. To investigate the genetic basis of human specializations in brain organization and cognition, we compared gene expression profiles for the cerebral cortex of humans, chimpanzees, and rhesus macaques by using several independent techniques. We identified 169 genes that exhibited expression differences between human and chimpanzee cortex, and 91 were ascribed to the human lineage by using macaques as an outgroup. Surprisingly, most differences between the brains of humans and non-human primates involved up-regulation, with ≈90% of the genes being more highly expressed in humans. By contrast, in the comparison of human and chimpanzee heart and liver, the numbers of up- and down-regulated genes were nearly identical. Our results indicate that the human brain displays a distinctive pattern of gene expression relative to non-human primates, with higher expression levels for many genes belonging to a wide variety of functional classes. The increased expression of these genes could provide the basis for extensive modifications of cerebral physiology and function in humans and suggests that the human brain is characterized by elevated levels of neuronal activity. PMID:14557539

  7. Induction of transplantation tolerance in non-human primate preclinical models

    PubMed Central

    Hale, Douglas A; Dhanireddy, Kiran; Bruno, David; Kirk, Allan D

    2005-01-01

    Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application. PMID:16147537

  8. 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

  9. The non-human primate reference transcriptome resource (NHPRTR) for comparative functional genomics

    PubMed Central

    Pipes, Lenore; Li, Sheng; Bozinoski, Marjan; Palermo, Robert; Peng, Xinxia; Blood, Phillip; Kelly, Sara; Weiss, Jeffrey M.; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Zumbo, Paul; Chen, Ronghua; Schroth, Gary P.; Mason, Christopher E.; Katze, Michael G.

    2013-01-01

    RNA-based next-generation sequencing (RNA-Seq) provides a tremendous amount of new information regarding gene and transcript structure, expression and regulation. This is particularly true for non-coding RNAs where whole transcriptome analyses have revealed that the much of the genome is transcribed and that many non-coding transcripts have widespread functionality. However, uniform resources for raw, cleaned and processed RNA-Seq data are sparse for most organisms and this is especially true for non-human primates (NHPs). Here, we describe a large-scale RNA-Seq data and analysis infrastructure, the NHP reference transcriptome resource (http://nhprtr.org); it presently hosts data from12 species of primates, to be expanded to 15 species/subspecies spanning great apes, old world monkeys, new world monkeys and prosimians. Data are collected for each species using pools of RNA from comparable tissues. We provide data access in advance of its deposition at NCBI, as well as browsable tracks of alignments against the human genome using the UCSC genome browser. This resource will continue to host additional RNA-Seq data, alignments and assemblies as they are generated over the coming years and provide a key resource for the annotation of NHP genomes as well as informing primate studies on evolution, reproduction, infection, immunity and pharmacology. PMID:23203872

  10. Detection of Optogenetic Stimulation in Somatosensory Cortex by Non-Human Primates - Towards Artificial Tactile Sensation

    PubMed Central

    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. PMID:25541938

  11. 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. PMID:24504856

  12. Functional definitions of parietal areas in human and non-human primates

    PubMed Central

    Orban, Guy A.

    2016-01-01

    Establishing homologies between cortical areas in animal models and humans lies at the heart of translational neuroscience, as it demonstrates how knowledge obtained from these models can be applied to the human brain. Here, we review progress in using parallel functional imaging to ascertain homologies between parietal areas of human and non-human primates, species sharing similar behavioural repertoires. The human homologues of several areas along monkey IPS involved in action planning and observation, such as AIP, LIP and CIP, as well as those of opercular areas (SII complex), have been defined. In addition, uniquely human areas, such as the tool-use area in left anterior supramarginal gyrus, have also been identified. PMID:27053755

  13. 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. PMID:23761751

  14. Airway gene transfer in a non-human primate: lentiviral gene expression in marmoset lungs.

    PubMed

    Farrow, N; Miller, D; Cmielewski, P; Donnelley, M; Bright, R; Parsons, D W

    2013-01-01

    Genetic therapies for cystic fibrosis (CF) must be assessed for safety and efficacy, so testing in a non-human primate (NHP) model is invaluable. In this pilot study we determined if the conducting airways of marmosets (n = 2) could be transduced using an airway pre-treatment followed by an intratracheal bolus dose of a VSV-G pseudotyped HIV-1 based lentiviral (LV) vector (LacZ reporter). LacZ gene expression (X-gal) was assessed after 7 days and found primarily in conducting airway epithelia as well as in alveolar regions. The LacZ gene was not detected in liver or spleen via qPCR. Vector p24 protein bio-distribution into blood was transient. Dosing was well tolerated. This preliminary study confirmed the transducibility of CF-relevant airway cell types. The marmoset is a promising NHP model for testing and translating genetic treatments for CF airway disease towards clinical trials. PMID:23412644

  15. 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.

  16. 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

  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. Study of the gastrointestinal parasitic fauna of captive non-human primates (Macaca fascicularis).

    PubMed

    Zanzani, Sergio Aurelio; Gazzonis, Alessia Libera; Epis, Sara; Manfredi, Maria Teresa

    2016-01-01

    The aim of this study was to examine helminths and protozoans in cynomolgus macaques (Macaca fascicularis) imported from registered breeding facilities in China and their relation to health risks for non-human primate handlers in biomedical research centers and in breeding facilities. Fresh fecal samples were collected from a total of 443 M. fascicularis and analyzed by copromicroscopical analysis, immunoenzymatic, or molecular assays. As to helminths, whose eggs were shed in 2.03% of the samples, Trichuris and Oesophagostomum were the only two taxa found, with low prevalence and low eggs per gram (EPG) values. Protozoans were more frequently detected (87.40%), with Entamoeba coli (85.19%) and Endolimax nana (79.26%) as the most prevalent species shed. Other parasites found by fecal smear examination were uninucleated-cyst-producing Entamoebas (78.52%), Iodamoeba bütschlii (42.96%), and Chilomastix mesnili (24.44%), while cysts of Balantidium coli (22.2%) were only observed by sedimentation. No coproantigens of Giardia duodenalis, Cryptosporidium spp., and Entamoeba histolytica complex were detected. Blastocystis sp. infection was noticed in 87.63% of macaques by PCR. These cynomolgus monkeys were infected with many subtypes (ST1, ST2, ST3, ST5, and ST7), where the predominant Blastocystis sp. subtypes were ST2 (77.5%), followed by ST1 (63.5%). Data collected confirmed the presence of potentially zoonotic parasites and a high parasite diversity, suggesting the need for appropriate and sensitive techniques to adequately control them and related health risks for handlers of non-human primates in biomedical research centers and in breeding facilities. PMID:26374536

  19. 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.

  20. Antigen dose escalation study of a VEGF-based therapeutic cancer vaccine in non human primates.

    PubMed

    Morera, Yanelys; Bequet-Romero, Mónica; Ayala, Marta; Pérez, Pedro Puente; Castro, Jorge; Sánchez, Javier; Alba, José Suárez; Ancízar, Julio; Cosme, Karelia; Gavilondo, Jorge V

    2012-01-01

    CIGB-247 is a cancer therapeutic, based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, in combination with the oil free adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). Our previous experimental studies in mice with CIGB-247 have shown that the vaccine has both anti-tumoral and anti-metastatic activity, and produces both antibodies that block VEGF-VEGF receptor interaction, and a specific T-cell cytotoxic response against tumor cells. CIGB-247, with an antigen dose of 100 μg, has been characterized by an excellent safety profile in mice, rats, rabbits, and non human primates. In this article we extend the immunogenicity and safety studies of CIGB-247 in non human primates, scaling the antigen dose from 100 μg to 200 and 400 μg/vaccination. Our results indicate that such dose escalation did not affect animal behavior, clinical status, and blood parameters and biochemistry. Also, vaccination did not interfere with skin deep skin wound healing. Anti-VEGF IgG antibodies and specific T-cell mediated responses were documented at all three studied doses. Antigen dose apparently did not determine differences in maximum antibody titer during the 8 weekly immunization induction phase, or the subsequent increase in antibodies seen for monthly boosters delivered afterwards. Higher antigen doses had a positive influence in antibody titer maintenance, after cessation of immunizations. Boosters were important to achieve maximum antibody VEGF blocking activity, and specific T-cell responses in all individuals. Purified IgG from CIGB-247 immunized monkey sera was able to impair proliferation and formation of capillary-like structures in Matrigel, for HMEC cells in culture. Altogether, these results support the further clinical development of the CIGB-247 therapeutic cancer vaccine, and inform on the potential mechanisms involved in its effect. PMID:22075086

  1. 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

  2. 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

  3. 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. PMID:25058455

  4. 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

  5. Concealed Fertility and Extended Female Sexuality in a Non-Human Primate (Macaca assamensis)

    PubMed Central

    Fürtbauer, Ines; Heistermann, Michael; Schülke, Oliver; Ostner, Julia

    2011-01-01

    In numerous primates living in mixed-sex groups, females display probabilistic cues of fertility to simultaneously concentrate paternity to dominant males while diluting it amongst others as a means to reduce the risk of infanticide and to increase male care for offspring. A few species, however, lack these cues and potentially conceal fertility from males; yet, to date, little is known about mating patterns and their underlying proximate mechanisms in such species. Here, we investigated mating activity and sexual consortships relative to female reproductive state in wild Assamese macaques (Macaca assamensis), a species where females lack prominent anogenital swellings and copulation calls. During two mating seasons (2837 contact hours) we recorded sexual and social behaviors, sexual consortships, and collected 1178 fecal samples (n = 15 females) which were analyzed for progestogen concentrations to assess female reproductive state and to determine the timing of ovulation and conception. Although mostly conceiving in their first ovarian cycle, females were sexually receptive throughout the entire 4-month mating season, and within-cycle mating frequencies were not increased during fertile phases. Dominant males did not monopolize fertile matings, and consortships by high-ranking males lasted for long periods, which were not exclusively linked to female fertile phases. Furthermore, females copulated promiscuously but not randomly, i.e. for almost every female, matings were concentrated to a certain male, irrespective of male rank. Collectively, we demonstrate that fertility is undisclosed to males. The extreme extended female sexuality facilitated by concealed fertility may allow females to create differentiated mating relationships within a promiscuous mating system. Our study provides important new insight into the plasticity of female sexuality in non-human primates. PMID:21853074

  6. Utility, Limitations, and Future of Non-Human Primates for Dengue Research and Vaccine Development

    PubMed Central

    Sariol, Carlos A.; White, Laura J.

    2014-01-01

    Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups. PMID:25309540

  7. 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

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

    PubMed

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

    2015-01-01

    Schistosomiasis remains a major cause of morbidity in the world. The challenge today is not so much in the clinical management of individual patients, but rather in population-based control of transmission in endemic areas. Despite recent large-scale efforts, such as integrated control programs aimed at limiting schistosomiasis by improving education and sanitation, molluscicide treatment programs and chemotherapy with praziquantel, there has only been limited success. There is an urgent need for complementary approaches, such as vaccines. We demonstrated previously that anti-oxidant enzymes, such as Cu-Zn superoxide dismutase (SOD) and glutathione S peroxidase (GPX), when administered as DNA-based vaccines induced significant levels of protection in inbred mice, greater than the target 40% reduction in worm burden compared to controls set as a minimum by the WHO. These results led us to investigate if immunization of non-human primates with antioxidants would stimulate an immune response that could confer protection as a prelude study for human trials. Issues of vaccine toxicity and safety that were difficult to address in mice were also investigated. All baboons in the study were examined clinically throughout the study and no adverse reactions occurred to the immunization. When our outbred baboons were vaccinated with two different formulations of SOD (SmCT-SOD and SmEC-SOD) or one of GPX (SmGPX), they showed a reduction in worm number to varying degrees, when compared with the control group. More pronounced, vaccinated animals showed decreased bloody diarrhea, days of diarrhea, and egg excretion (transmission), as well as reduction of eggs in the liver tissue and in the large intestine (pathology) compared to controls. Specific IgG antibodies were present in sera after immunizations and 10 weeks after challenge infection compared to controls. Peripheral blood mononuclear cells, mesenteric, and inguinal node cells from vaccinated animals proliferated and

  9. 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

    Schistosomiasis remains a major cause of morbidity in the world. The challenge today is not so much in the clinical management of individual patients, but rather in population-based control of transmission in endemic areas. Despite recent large-scale efforts, such as integrated control programs aimed at limiting schistosomiasis by improving education and sanitation, molluscicide treatment programs and chemotherapy with praziquantel, there has only been limited success. There is an urgent need for complementary approaches, such as vaccines. We demonstrated previously that anti-oxidant enzymes, such as Cu–Zn superoxide dismutase (SOD) and glutathione S peroxidase (GPX), when administered as DNA-based vaccines induced significant levels of protection in inbred mice, greater than the target 40% reduction in worm burden compared to controls set as a minimum by the WHO. These results led us to investigate if immunization of non-human primates with antioxidants would stimulate an immune response that could confer protection as a prelude study for human trials. Issues of vaccine toxicity and safety that were difficult to address in mice were also investigated. All baboons in the study were examined clinically throughout the study and no adverse reactions occurred to the immunization. When our outbred baboons were vaccinated with two different formulations of SOD (SmCT-SOD and SmEC-SOD) or one of GPX (SmGPX), they showed a reduction in worm number to varying degrees, when compared with the control group. More pronounced, vaccinated animals showed decreased bloody diarrhea, days of diarrhea, and egg excretion (transmission), as well as reduction of eggs in the liver tissue and in the large intestine (pathology) compared to controls. Specific IgG antibodies were present in sera after immunizations and 10 weeks after challenge infection compared to controls. Peripheral blood mononuclear cells, mesenteric, and inguinal node cells from vaccinated animals proliferated and

  10. [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

  11. A word in the hand: action, gesture and mental representation in humans and non-human primates

    PubMed Central

    Cartmill, Erica A.; Beilock, Sian; Goldin-Meadow, Susan

    2012-01-01

    The movements we make with our hands both reflect our mental processes and help to shape them. Our actions and gestures can affect our mental representations of actions and objects. In this paper, we explore the relationship between action, gesture and thought in both humans and non-human primates and discuss its role in the evolution of language. Human gesture (specifically representational gesture) may provide a unique link between action and mental representation. It is kinaesthetically close to action and is, at the same time, symbolic. Non-human primates use gesture frequently to communicate, and do so flexibly. However, their gestures mainly resemble incomplete actions and lack the representational elements that characterize much of human gesture. Differences in the mirror neuron system provide a potential explanation for non-human primates' lack of representational gestures; the monkey mirror system does not respond to representational gestures, while the human system does. In humans, gesture grounds mental representation in action, but there is no evidence for this link in other primates. We argue that gesture played an important role in the transition to symbolic thought and language in human evolution, following a cognitive leap that allowed gesture to incorporate representational elements. PMID:22106432

  12. Genetic heterogeneity and phylogeny of Trichuris spp. from captive non-human primates based on ribosomal DNA sequence data.

    PubMed

    Cavallero, Serena; De Liberato, Claudio; Friedrich, Klaus G; Di Cave, David; Masella, Valentina; D'Amelio, Stefano; Berrilli, Federica

    2015-08-01

    Nematodes of the genus Trichuris, known as whipworms, are recognized to infect numerous mammalian species including humans and non-human primates. Several Trichuris spp. have been described and species designation/identification is traditionally based on host-affiliation, although cross-infection and hybridization events may complicate species boundaries. The main aims of the present study were to genetically characterize adult Trichuris specimens from captive Japanese macaques (Macaca fuscata) and grivets (Chlorocebus aethiops), using the ribosomal DNA (ITS) as molecular marker and to investigate the phylogeny and the extent of genetic variation also by comparison with data on isolates from other humans, non-human primates and other hosts. The phylogenetic analysis of Trichuris sequences from M. fuscata and C. aethiops provided evidences of distinct clades and subclades thus advocating the existence of additional separated taxa. Neighbor Joining and Bayesian trees suggest that specimens from M. fuscata may be distinct from, but related to Trichuris trichiura, while a close relationship is suggested between the subclade formed by the specimens from C. aethiops and the subclade formed by T. suis. The tendency to associate Trichuris sp. to host species can lead to misleading taxonomic interpretations (i.e. whipworms found in primates are identified as T. trichiura). The results here obtained confirm previous evidences suggesting the existence of Trichuris spp. other than T. trichiura infecting non-human living primates. PMID:26066463

  13. 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

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

    PubMed Central

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

    2013-01-01

    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 (2–10 s) 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. PMID:22967858

  15. Measuring pad-pad pinch strength in a non-human primate: Macaca fascicularis.

    PubMed

    Banks, Jacob J; Lavender, Steven A; Buford, John A; Sommerich, Carolyn M

    2007-12-01

    The primary purpose of this study was to establish a methodology for determining and perhaps predicting (via regression analysis of anthropometric measures) Macaca fascicularis isometric pinch strength for a specific task. The larger purpose of this work was to properly scale a pinching task for the monkeys in order to study dose-response relationships in a non-human primate model for carpal tunnel syndrome. Three female and one male macaque (n=4) of varying size and age were trained to perform a left-handed pad-pad pinch. The task required 60 degrees of wrist flexion at a static pinching distance of 3 cm between the thumb and fingers. Subjects were trained for a period of 20-weeks. After that time, an analysis of performance gradients found that they had each reached a plateau in their force output. Pinch strength for the four animals ranged from 29.4 to 59.8 N. Regression analysis revealed that body mass (kg) and wrist circumference (cm) were both predictive of pinch strength, exhibiting adjusted R(2) values of 0.93 (p=0.024) and 0.96 (p=0.015), respectively. Thus, the results suggest that maximal pinch strength could be acceptably estimated in future subjects using either the wrist circumference or the body mass measures, as both were strong predictors of pad-pad pinch strength. PMID:17035044

  16. 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. PMID:25533326

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

    PubMed Central

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

    2014-01-01

    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 B. thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ~1×104 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 titres 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. PMID:25533326

  18. Neurovirulence Properties of Recombinant Vesicular Stomatitis Virus Vectors in Non-Human Primates

    PubMed Central

    Johnson, J. Erik; Nasar, Farooq; Coleman, John W.; Price, Roger E.; Javadian, Ali; Draper, Kenneth; Lee, Margaret; Reilly, Patricia A.; Clarke, David K.; Hendry, R. Michael; Udem, Stephen A.

    2007-01-01

    Although vesicular stomatitis virus (VSV) neurovirulence and pathogenicity in rodents have been well studied, little is known about VSV pathogenicity in non-human primates. To address this question, we measured VSV viremia, shedding, and neurovirulence in macaques. Following intranasal inoculation, macaques shed minimal recombinant VSV (rVSV) in nasal washes for one day post-inoculation; viremia was not detected. Following intranasal inoculation of macaques, wild type (wt) VSV, rVSV, and two rVSV-HIV vectors showed no evidence of spread to CNS tissues. However, macaques inoculated intrathalamically with wt VSV developed severe neurological disease. One of four macaques receiving rVSV developed clinical and histological signs similar to the wt group, while the remaining three macaques in this group and all of the macaques in the rVSV-HIV vector groups showed no clinical signs of disease and reduced severity of histopathology compared to the wt group. The implications of these findings for rVSV vaccine development are discussed. PMID:17098273

  19. Non-invasive ultrasonic surgery of the brain in non-human primates.

    PubMed

    Marquet, Fabrice; Boch, Anne-Laure; Pernot, Mathieu; Montaldo, Gabriel; Seilhean, Danielle; Fink, Mathias; Tanter, Mickael; Aubry, Jean-Francois

    2013-08-01

    High-intensity focused ultrasound causes selective tissue necrosis efficiently and safely, namely, in the prostate, liver, and uterine fibroid. Nevertheless, ablation of brain tissue using focused ultrasound remains limited due to strong aberrations induced by the skull. To achieve ultrasonic transcranial brain ablation, such aberrations have to be compensated. In this study, non-invasive therapy was performed on monkeys using adaptive correction of the therapeutic beam and 3D simulations of transcranial wave propagation based on 3D computed tomographic (CT) scan information. The aim of the study was two-fold: induce lesions in a non-human primate brain non-invasively and investigate the potential side effects. Stereotactic targeting was performed on five Macaca fascicularis individuals. Each hemisphere was treated separately with a 15-day interval and animals were sacrificed two days after the last treatment. The ultrasonic dose delivered at the focus was increased from one treatment location to the other to estimate the thermal dose for tissue alteration. Thermal doses in the brain were determined by numerical computations. Treatment efficiency and safety were evaluated histologically. The threshold for tissue damage in the brain was measured to be between 90 and 280 cumulative equivalent minutes at 43 °C. Intravenous injection of corticoids before the treatment limited the side effects. PMID:23927203

  20. Vocal turn-taking in a non-human primate is learned during ontogeny

    PubMed Central

    Chow, Cecilia P.; Mitchell, Jude F.; Miller, Cory T.

    2015-01-01

    Conversational turn-taking is an integral part of language development, as it reflects a confluence of social factors that mitigate communication. Humans coordinate the timing of speech based on the behaviour of another speaker, a behaviour that is learned during infancy. While adults in several primate species engage in vocal turn-taking, the degree to which similar learning processes underlie its development in these non-human species or are unique to language is not clear. We recorded the natural vocal interactions of common marmosets (Callithrix jacchus) occurring with both their sibling twins and parents over the first year of life and observed at least two parallels with language development. First, marmoset turn-taking is a learned vocal behaviour. Second, marmoset parents potentially played a direct role in guiding the development of turn-taking by providing feedback to their offspring when errors occurred during vocal interactions similarly to what has been observed in humans. Though species-differences are also evident, these findings suggest that similar learning mechanisms may be implemented in the ontogeny of vocal turn-taking across our Order, a finding that has important implications for our understanding of language evolution. PMID:25904663

  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. PMID:27031602

  2. Transcriptomal changes and functional annotation of the developing non-human primate choroid plexus

    PubMed Central

    Ek, C. Joakim; Nathanielsz, Peter; Li, Cun; Mallard, Carina

    2015-01-01

    The choroid plexuses are small organs that protrude into each brain ventricle producing cerebrospinal fluid that constantly bathes the brain. These organs differentiate early in development just after neural closure at a stage when the brain is little vascularized. In recent years the plexus has been shown to have a much more active role in brain development than previously appreciated thereby it can influence both neurogenesis and neural migration by secreting factors into the CSF. However, much of choroid plexus developmental function is still unclear. Most previous studies on this organ have been undertaken in rodents but translation into humans is not straightforward since they have a different timing of brain maturation processes. We have collected choroid plexus from three fetal gestational ages of a non-human primate, the baboon, which has much closer brain development to humans. The transcriptome of the plexuses was determined by next generation sequencing and Ingenuity Pathway Analysis software was used to annotate functions and enrichment of pathways of changes in the transcriptome. The number of unique transcripts decreased with development and the majority of differentially expressed transcripts were down-regulated through development suggesting a more complex and active plexus earlier in fetal development. The functional annotation indicated changes across widespread biological functions in plexus development. In particular we find age-dependent regulation of genes associated with annotation categories: Gene Expression, Development of Cardiovascular System, Nervous System Development and Molecular Transport. Our observations support the idea that the choroid plexus has roles in shaping brain development. PMID:25814924

  3. Cortical Innervation of the Hypoglossal Nucleus in the Non-Human Primate (Macaca mulatta)

    PubMed Central

    Morecraft, Robert J.; Stilwell-Morecraft, Kimberly S.; Solon-Cline, Kathryn M.; Ge, Jizhi; Darling, Warren G.

    2014-01-01

    The corticobulbar projection to the hypoglossal nucleus was studied from the frontal, parietal, cingulate and insular cortices in the rhesus monkey using high-resolution anterograde tracers and stereology. The hypoglossal nucleus received bilateral input from the face/head region of the primary (M1), ventrolateral pre- (LPMCv), supplementary (M2), rostral cingulate (M3), and caudal cingulate (M4) motor cortices. Additional bilateral corticohypoglossal projections were found from the dorsolateral premotor cortex (LPMCd), ventrolateral proisocortical motor area (ProM), ventrolateral primary somatosensory cortex (S1), rostral insula and pregenual region of the anterior cingulate gyrus (areas 24/32). Dense terminal projections arose from the ventral region of M1, moderate projections from LPMCv and rostral part of M2, with considerably less hypoglossal projections arising from the other cortical regions. These findings demonstrate that extensive regions of the non-human primate cerebral cortex innervate the hypoglossal nucleus. The widespread and bilateral nature of this corticobulbar connection suggests recovery of tongue movement after cortical injury that compromises a subset of these areas, may occur from spared corticohypoglossal projection areas located on the lateral, as well as medial surfaces of both hemispheres. Since functional imaging studies have shown that homologous cortical areas are activated in humans during tongue movement tasks, these corticobulbar projections may exist in the human brain. PMID:24752643

  4. 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

  5. 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

    2016-01-01

    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

  6. Non-Human Primates Harbor Diverse Mammalian and Avian Astroviruses Including Those Associated with Human Infections

    PubMed Central

    Freiden, Pamela; Feeroz, MM; Matsen, Frederick A; San, Sorn; Hasan, M Kamrul; Wang, David; Jones-Engel, Lisa; Schultz-Cherry, Stacey

    2015-01-01

    Astroviruses (AstVs) are positive sense, single-stranded RNA viruses transmitted to a wide range of hosts via the fecal-oral route. The number of AstV-infected animal hosts has rapidly expanded in recent years with many more likely to be discovered because of the advances in viral surveillance and next generation sequencing. Yet no study to date has identified human AstV genotypes in animals, although diverse AstV genotypes similar to animal-origin viruses have been found in children with diarrhea and in one instance of encephalitis. Here we provide important new evidence that non-human primates (NHP) can harbor a wide variety of mammalian and avian AstV genotypes, including those only associated with human infection. Serological analyses confirmed that >25% of the NHP tested had antibodies to human AstVs. Further, we identified a recombinant AstV with parental relationships to known human AstVs. Phylogenetic analysis suggests AstVs in NHP are on average evolutionarily much closer to AstVs from other animals than are AstVs from bats, a frequently proposed reservoir. Our studies not only demonstrate that human astroviruses can be detected in NHP but also suggest that NHP are unique in their ability to support diverse AstV genotypes, further challenging the paradigm that astrovirus infection is species-specific. PMID:26571270

  7. Wearable wireless sensor platform for studying autonomic activity and social behavior in non-human primates.

    PubMed

    Fletcher, Richard Ribón; Amemori, Ken-ichi; Goodwin, Matthew; Graybiel, Ann M

    2012-01-01

    A portable system has been designed to enable remote monitoring of autonomic nervous system output in non-human primates for the purpose of studying neural function related to social behavior over extended periods of time in an ambulatory setting. In contrast to prior systems which only measure heart activity, are restricted to a constrained laboratory setting, or require surgical attachment, our system is comprised of a multi-sensor self-contained wearable vest that can easily be transferred from one subject to another. The vest contains a small detachable low-power electronic sensor module for measuring electrodermal activity (EDA), electrocardiography (ECG), 3-axis acceleration, and temperature. The wireless transmission is implemented using a standard Bluetooth protocol and a mobile phone, which enables freedom of movement for the researcher as well as for the test subject. A custom Android software application was created on the mobile phone for viewing and recording live data as well as creating annotations. Data from up to seven monkeys can be recorded simultaneously using the mobile phone, with the option of real-time upload to a remote web server. Sample data are presented from two rhesus macaque monkeys showing stimulus-induced response in the laboratory as well as long-term ambulatory data collected in a large monkey cage. This system enables new possibilities for studying underlying mechanisms between autonomic brain function and social behavior with connection to human research in areas such as autism, substance abuse, and mood disorders. PMID:23366816

  8. Transcriptomal changes and functional annotation of the developing non-human primate choroid plexus.

    PubMed

    Ek, C Joakim; Nathanielsz, Peter; Li, Cun; Mallard, Carina

    2015-01-01

    The choroid plexuses are small organs that protrude into each brain ventricle producing cerebrospinal fluid that constantly bathes the brain. These organs differentiate early in development just after neural closure at a stage when the brain is little vascularized. In recent years the plexus has been shown to have a much more active role in brain development than previously appreciated thereby it can influence both neurogenesis and neural migration by secreting factors into the CSF. However, much of choroid plexus developmental function is still unclear. Most previous studies on this organ have been undertaken in rodents but translation into humans is not straightforward since they have a different timing of brain maturation processes. We have collected choroid plexus from three fetal gestational ages of a non-human primate, the baboon, which has much closer brain development to humans. The transcriptome of the plexuses was determined by next generation sequencing and Ingenuity Pathway Analysis software was used to annotate functions and enrichment of pathways of changes in the transcriptome. The number of unique transcripts decreased with development and the majority of differentially expressed transcripts were down-regulated through development suggesting a more complex and active plexus earlier in fetal development. The functional annotation indicated changes across widespread biological functions in plexus development. In particular we find age-dependent regulation of genes associated with annotation categories: Gene Expression, Development of Cardiovascular System, Nervous System Development and Molecular Transport. Our observations support the idea that the choroid plexus has roles in shaping brain development. PMID:25814924

  9. Surface roughness enhances the osseointegration of titanium headposts in non-human primates.

    PubMed

    Hacking, S A; Boyraz, P; Powers, B M; Sen-Gupta, E; Kucharski, W; Brown, C A; Cook, E P

    2012-11-15

    It is well recognized that micrometer and nanometer sized surface features enhance the skeletal attachment of implants within bone. However, little is known regarding the integration of implants placed outside the bone but in contact with the surface. Loosening of chronic skull anchored headposts in non-human primate based experiments can be a factor. The purpose of this study was to evaluate the effect of a simple and easily applied surface texture on bone apposition to titanium implants fixed to the periosteal surface of the skull. Implants possessed either a polished surface or a textured surface created by grit-basting followed by acid etching. The percent of bone in contact with the implant surface (bone apposition) to three polished and three textured implants was evaluated in one adult female monkey after 14 weeks. Upon harvest, implants were processed for undecalcified histology and regions of bone apposition were quantified using backscatter electron microscopy and digital image analysis. The bone apposition to textured implants was 62±20% and to polished implants was 42±21%. The application of a peak-and-pit like texture to the surface of titanium implants significantly increased bone apposition to titanium implants placed on the periosteal surface of the skull. This study demonstrates that titanium headposts can easily be modified to improve osseointegration using equipment and supplies available to most neurophysiological laboratories. In addition, implant texturing may have utility in areas including skeletal trauma and reconstruction where devices are placed in contact with the bone surface. PMID:22975472

  10. 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

  11. 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. PMID:26077889

  12. 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. PMID:24304306

  13. Characterization of alveolar macrophage eicosanoid production in a non-human primate model of mineral dust exposure.

    PubMed

    Kuhn, D C; Griffith, J W; Stauffer, J L; Riling, S; Demers, L M

    1993-09-01

    The relative activation of eicosanoid production which results from the exposure of the alveolar macrophage (AM) to mineral dusts is thought to be a key factor in the pathophysiology of occupational lung disease. We compared in vitro basal and silica-stimulated production of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) by AM from normal humans and non-human primates (Macaca nemestrina). In addition, we instilled mineral dusts directly into one lung of the non-human primate and evaluated AM eicosanoid production at two week intervals following dust instillation. Unstimulated AM from humans produce more PGE2 and TXA2 than do AM from M. nemestrina. However, in vitro exposure of AM from both species to silica dust produced a qualitatively similar increase in TXA2 production accompanied by no change in PGE2 production. Sequential analysis of AM eicosanoid production following a single bolus exposure to bituminous or anthracite coal dusts, titanium dioxide (TiO2) dust or crystalline silica showed marked variability among individual non-human primates in qualitative and quantitative aspects of dust-induced eicosanoid production. However, the rank order of potency of the different dusts (silica > anthracite > bituminous) correlated with epidemiological evidence relating the type of dust mined to the incidence of pneumoconiosis. These studies suggest that the non-human primate may serve as a model for the study of both the role of eicosanoids in the etiology of dust-induced occupational lung disease and the biochemical basis for individual variability in the response of lung cells to mineral dust exposure. PMID:8234829

  14. 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. PMID:27627203

  15. 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.

  16. 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. PMID:26323837

  17. 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

  18. 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

  19. Neuroanatomical Study of the A11 Diencephalospinal Pathway in the Non-Human Primate

    PubMed Central

    Barraud, Quentin; Obeid, Ibrahim; Aubert, Incarnation; Barrière, Gregory; Contamin, Hugues; McGuire, Steve; Ravenscroft, Paula; Porras, Gregory; Tison, François; Bezard, Erwan; Ghorayeb, Imad

    2010-01-01

    Background The A11 diencephalospinal pathway is crucial for sensorimotor integration and pain control at the spinal cord level. When disrupted, it is thought to be involved in numerous painful conditions such as restless legs syndrome and migraine. Its anatomical organization, however, remains largely unknown in the non-human primate (NHP). We therefore characterized the anatomy of this pathway in the NHP. Methods and Findings In situ hybridization of spinal dopamine receptors showed that D1 receptor mRNA is absent while D2 and D5 receptor mRNAs are mainly expressed in the dorsal horn and D3 receptor mRNA in both the dorsal and ventral horns. Unilateral injections of the retrograde tracer Fluoro-Gold (FG) into the cervical spinal enlargement labeled A11 hypothalamic neurons quasi-exclusively among dopamine areas. Detailed immunohistochemical analysis suggested that these FG-labeled A11 neurons are tyrosine hydroxylase-positive but dopa-decarboxylase and dopamine transporter-negative, suggestive of a L-DOPAergic nucleus. Stereological cell count of A11 neurons revealed that this group is composed by 4002±501 neurons per side. A 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxication with subsequent development of a parkinsonian syndrome produced a 50% neuronal cell loss in the A11 group. Conclusion The diencephalic A11 area could be the major source of L-DOPA in the NHP spinal cord, where it may play a role in the modulation of sensorimotor integration through D2 and D3 receptors either directly or indirectly via dopamine formation in spinal dopa-decarboxylase-positives cells. PMID:20967255

  20. 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).

  1. Evolution of the CYP2D gene cluster in humans and four non-human primates.

    PubMed

    Yasukochi, Yoshiki; Satta, Yoko

    2011-01-01

    The human cytochrome P450 2D6 (CYP2D6) is a primary enzyme involved in the metabolism of about 25% of commonly used therapeutic drugs. CYP2D6 belongs to the CYP2D subfamily, a gene cluster located on chromosome 22, which comprises the CYP2D6 gene and pseudogenes CYP2D7P and CYP2D8P. Although the chemical and physiological properties of CYP2D6 have been extensively studied, there has been no study to date on molecular evolution of the CYP2D subfamily in the human genome. Such knowledge could greatly contribute to the understanding of drug metabolism in humans because it makes us to know when and how the current metabolic system has been constructed. The knowledge moreover can be useful to find differences in exogenous substrates in a particular metabolism between human and other animals such as experimental animals. Here, we conducted a preliminary study to investigate the evolution and gene organization of the CYP2D subfamily, focused on humans and four non-human primates (chimpanzees, orangutans, rhesus monkeys, and common marmosets). Our results indicate that CYP2D7P has been duplicated from CYP2D6 before the divergence between humans and great apes, whereas CYP2D6 and CYP2D8P have been already present in the stem lineages of New World monkeys and Catarrhini. Furthermore, the origin of the CYP2D subfamily in the human genome can be traced back to before the divergence between amniotes and amphibians. Our analyses also show that reported chimeric sequences of the CYP2D6 and CYP2D7 genes in the chimpanzee genome appear to be exchanged in its genome database. PMID:21670550

  2. 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

  3. 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. PMID:25684556

  4. 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

  5. A non-human primate model of bipedal locomotion under restrained condition allowing gait studies and single unit brain recordings.

    PubMed

    Goetz, L; Piallat, B; Thibaudier, Y; Montigon, O; David, O; Chabardès, S

    2012-03-15

    For decades, several animal models of locomotion have allowed a better understanding of the basic physiological mechanisms of gait. However, unlike most of the mammals, the Order Primates is characterized by fundamental changes in locomotor behaviour. In particular, some primates use a specific pattern of locomotion and are able to naturally walk bipedally due possibly to a specific supra-spinal control of locomotion. These features must be taken into account when one considers to study the intrinsic properties of human gait. Thus, an experimental model of bipedal locomotion allowing precise and reproducible analysis of gait in non-human primate is still lacking. This study describes a non-human primate model of bipedal locomotion under restrained condition. We undertook a kinematic and biomechanic study in three Macaca fascicularis trained to walk bipedally on a treadmill. One of the primate was evaluated in complete head fixation. Gait visual analysis and electromyographic recordings provided pertinent description of the gait pattern. Step frequencies, step lengths, cycle and stance phase durations were correlated with Froude number (dimensionless velocity), whereas swing phase durations remained non-correlated. Gait patterns observed in our model were similar to those obtained in freely bipedal Macaca fuscata and to a lesser extend to Humans. Gait pattern was not modified by head fixation thereby allowing us to perform precise and repetitive micro electrode recordings of deep cerebral structures. Thus, the present model could provide a pertinent pre-clinical tool to study gait parameters and their neuronal control but also could be helpful to validate new therapeutics interventions. PMID:22155386

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Age-Related Degenerative Functional, Radiographic, and Histological Changes of the Shoulder in Non-Human Primates

    PubMed Central

    Plate, Johannes F.; Bates, Christopher M.; Mannava, Sandeep; Smith, Thomas L.; Jorgensen, Matthew J.; Register, Thomas C.; Stehle, John R.; High, Kevin P.; Shively, Carol A.; Kaplan, Jay R.; Saul, Katherine R.; Tuohy, Christopher J.

    2013-01-01

    Background Non-human primates have similar shoulder anatomy and physiology compared to humans and may represent a previously underutilized model for shoulder research. This study sought to identify naturally occurring bony and muscular degeneration in the shoulder of non-human primates and to assess relationships between structural and functional aspects of the shoulder and measures of physical function of the animals. We hypothesized that age-related degenerative changes in the shoulders of non-human primates would resemble those observed in aging humans. Methods Middle-aged (n=5, ages 9.4 to 11.8 years) and elderly (n=6, ages 19.8 to 26.4 years) female vervet monkeys were studied for changes in mobility and shoulder function, and radiographic and histologic signs of age-related degeneration. Results Four out of six (4/6) elderly animals had degenerative changes of the glenoid compared to 0/5 of the middle-aged animals (p=0.005). Elderly animals had glenoid retroversion, decreased joint space, walked slower and spent less time climbing and hanging than middle-aged vervets (p<0.05). Physical mobility and shoulder function correlated with glenoid version angle (p<0.05). Supraspinatus muscles of elderly animals were less dense (p=0.001), had decreased fiber cross-sectional area (p<0.001), but similar amounts of nuclear material (p=0.085). Degenerative rotator cuff tears were not observed in any of the eleven animals. Discussion and Conclusion The vervet monkey naturally undergoes age-related functional, radiographic and histological changes of the shoulder and may qualify as an animal model for selected translational research of shoulder osteoarthritis. Level of evidence Basic Science Study, in-vivo Animal Model PMID:23352182

  14. Ethical review of projects involving non-human primates funded under the European Union's 7th Research Framework Programme.

    PubMed

    Sauer, Ursula; Phillips, Barry; Reid, Kirsty; Schmit, Véronique; Jennings, Maggy

    2013-09-01

    Internet searches were performed on projects involving non-human primates ('primates') funded under the European Union (EU) 7th Research Framework Programme (FP7), to determine how project proposals are assessed from an ethical point of view. Due to the incompleteness of the information publicly available, the types and severity of the experiments could not be determined with certainty, although in some projects the level of harm was considered to be 'severe'. Information was scarce regarding the numbers of primates, their sourcing, housing, care and fate, or the application of the Three Rs within projects. Project grant holders and the relevant Commission officer were consulted about their experiences with the FP7 ethics review process. Overall, it was seen as meaningful and beneficial, but some concerns were also noted. Ethical follow-up during project performance and upon completion was recognised as a valuable tool in ensuring that animal welfare requirements were adequately addressed. Based upon the outcome of the survey, recommendations are presented on how to strengthen the ethical review process under the upcoming Framework Programme 'Horizon 2020', while adequately taking into account the specific requirements of Directive 2010/63/EU, with the aim of limiting the harms inflicted on the animals and the numbers used, and ultimately, replacing the use of primates altogether. PMID:24168134

  15. 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

  16. The detection limits for estimates of infection intensity in schistosomiasis mansoni established by a study in non-human primates.

    PubMed

    Alan Wilson, R; van Dam, Govert J; Kariuki, Thomas M; Farah, Idle O; Deelder, André M; Coulson, Patricia S

    2006-10-01

    In human schistosomiasis mansoni, it is impossible to directly determine worm burden and hence infection intensity, so surrogates must be used. Studies on non-human primates revealed a linear relationship between worm burden and three surrogates, faecal egg output, circulating anodic and circulating cathodic antigens. By regression, the thresholds of detection were determined as 40, 24 and 47 worms, respectively. These observations provide a quantitative basis for the contention that low intensity infections in humans are being missed. The significance for estimates of disease prevalence, evaluation of the effects of chemotherapy and the implementation of vaccine trials is emphasised. PMID:16930605

  17. Caring for non-human primates in biomedical research facilities: scientific, moral and emotional considerations

    PubMed Central

    Coleman, Kristine

    2010-01-01

    Animal care for nonhuman primates in biomedical facilities has undergone major changes in the past few decades. Today, most primate facilities have dedicated and highly trained animal care technicians who go to great efforts to ensure the physiological and psychological well being of the primates in their charge. These caretakers work closely with the animals, and as a result, often develop strong relationships with them. Once discouraged and considered a potential threat to scientific objectivity, such positive relationships are now seen as important components to animal care. Positive interactions between caretakers and primates can benefit the primates by reducing their stress and improving their overall well-being which can, in turn, help the scientific endeavor. Further, providing the best possible care is our moral responsibility. However, there can also be emotional costs associated with caring for nonhuman primates in research facilities, particularly when animals become ill or have to be euthanized. Facilities can do much to help ease this conflict. High quality and conscientious animal care is good for the animals, good for the science, and good for public perception of research facilities. PMID:20575044

  18. 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

  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. 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". PMID:23994296

  1. Biocompatibility Assessment of Detonation Nanodiamond in Non-Human Primates and Rats Using Histological, Hematologic, and Urine Analysis.

    PubMed

    Moore, Laura; Yang, Junyu; Lan, Thanh T Ha; Osawa, Eiji; Lee, Dong-Keun; Johnson, William D; Xi, Jianzhong; Chow, Edward Kai-Hua; Ho, Dean

    2016-08-23

    Detonation nanodiamonds (DNDs) have been widely explored for biomedical applications ranging from cancer therapy to magnetic resonance imaging due to several promising properties. These include faceted surfaces that mediate potent drug binding and water coordination that have resulted in marked enhancements to the efficacy and safety of drug delivery and imaging. In addition, scalable processing of DNDs yields uniform particles. Furthermore, a broad spectrum of biocompatibility studies has shown that DNDs appear to be well-tolerated. Prior to the clinical translation of DNDs for indications that are addressed via intravenous administration, comprehensive assessment of DND safety in both small and large animal preclinical models is needed. This article reports the results of a DND biocompatibility study in both non-human primates and rats. The rat study was performed as a multiple dose subacute investigation in two cohorts that lasted for 2 weeks and included histological, serum, and urine analysis. The non-human primate study was performed as a dual gender, multiple dose, and long-term investigation in both standard/clinically relevant and elevated dosing cohorts that lasted for 6 months and included comprehensive serum, urine, histological, and body weight analysis. The results from these studies indicate that NDs are well-tolerated at clinically relevant doses. Examination of dose-dependent changes in biomarker levels provides important guidance for the downstream in-human validation of DNDs for clinical drug delivery and imaging. PMID:27439019

  2. 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. PMID:26045343

  3. Evolution of the sweetness receptor in primates. II. Gustatory responses of non-human primates to nine compounds known to be sweet in man.

    PubMed

    Nofre, C; Tinti, J M; Glaser, D

    1996-12-01

    The gustatory responses of nine compounds, namely glycine, D-phenylalanine, D-tryptophan, cyanosuosan, magapame, sucrononate, campame, cyclamate and superaspartame, all known as sweet in man, were studied in 41 species or subspecies of non-human primates, selected among Prosimii (Lemuridae and Lorisidae), Platyrrhini (Callitrichidae and Cebidae) and Catarrhini (Cercopithecidae, Hylobatidae and Pongidae). The first six compounds are generally sweet to all primates, which implies that they interact with the primate sweetness receptors essentially through constant recognition sites. Campame is sweet only to Cebidae and Catarrhini, cyclamate only to Catarrhini, superaspartame principally to Callitrichidae and Catarrhini, which implies that all these compounds interact with the receptors partly through variable recognition sites. From the present work, from other previous results (where notably it was observed that alitame is sweet to all primates, ampame only to Prosimii and Catarrhini, and aspartame only to Catarrhini), and from the multipoint attachment (MPA) theory of sweetness reception (as elaborated by Nofre and Tinti from a detailed study of structure-activity relationships of various sweeteners in man), it is inferred that the primate sweetness receptors are very likely made up of eight recognition sites, of which the first, second, third, fourth, seventh and eighth are constant, and the fifth and sixth variable. From these results and from the MPA theory, it is also inferred that the recognition sites of the primate sweetness receptors could be: Asp-1 or Glu-1, Lys-2, Asp-3 or Glu-3, Thr-4, X-5, X-6, Thr-7, Ser-8, where the variable recognition sites X-5 and X-6 would be: Ala-5 and Ala-6 for Callitrichidae, Ser-5 and Ala-6 for Cebidae, Ala-5 and Thr-6 for Prosimii, and Thr-5 and Thr-6 for Catarrhini. By using Tupaiidae (tree shrews) as a reference outgroup and by means of other structural and functional molecular considerations, it appears that Callitrichidae

  4. 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. PMID:25541938

  5. Overlapping expression of anion exchangers in the cochlea of a non-human primate suggests functional compensation.

    PubMed

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

    2016-09-01

    Ion homeostasis in the inner ear is essential for proper hearing. Anion exchangers are one of the transporters responsible for the maintenance of homeostasis, but their expression profile in the primate cochlea has not been fully characterized. However, species-specific overlapping expression patterns and functional compensation in other organs, such as the kidney, pancreas and small intestine, have been reported. Here, we determined the expression patterns of the anion exchangers SLC26A4, SLC26A5, SLC26A6, SLC26A7, SLC26A11, SLC4A2 and SLC4A3 in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). Although the pattern of expression of SLC26A4 and SLC26A5 was similar to that in rodents, SLC26A7, SLC4A2, SLC4A3 exhibited different distributions. Notably, five transporters, SLC26A4, SLC26A6, SLC26A11 SLC4A2 and SLC4A3, were expressed in the cells of the outer sulcus. Our results reveal a species-specific distribution pattern of anion exchangers in the cochlea, particularly in the outer sulcus cells, suggesting functional compensation among these exchangers. This "primate-specific" pattern may be related to the human-specific hearing loss phenotypes of channelopathy disorders, including the SLC26A4-related diseases Pendred syndrome/DFNB4. PMID:27091614

  6. 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. PMID:26884274

  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. The aging baboon: comparative demography in a non-human primate.

    PubMed

    Bronikowski, Anne M; Alberts, Susan C; Altmann, Jeanne; Packer, Craig; Carey, K Dee; Tatar, Marc

    2002-07-01

    Why do closely related primate genera vary in longevity, and what does this teach us about human aging? Life tables of female baboons (Papio hamadryas) in two wild populations of East Africa and in a large captive population in San Antonio, Texas, provide striking similarities and contrasts to human mortality patterns. For captive baboons at the Southwest Foundation for Biomedical Research, we estimate the doubling time of adult mortality rate as 4.8 years. Wild females in free-living populations in Tanzania and in Kenya showed doubling times of 3.5 and 3.8 years, respectively. Although these values are considerably faster than the estimates of 7-8 years for humans, these primates share a demographic feature of human aging: within each taxon populations primarily vary in the level of Gompertz mortality intercept (frailty) and vary little in the demographic rate of aging. Environmental and genetic factors within taxa appear to affect the level of frailty underlying senescence. In contrast, primate taxa are differentiated by rates of demographic aging, even if they cannot be characterized by species-specific lifespan. PMID:12082185

  9. Ageing as a primary risk factor for Parkinson’s disease: evidence from studies of non-human primates

    PubMed Central

    Collier, Timothy J.; Kanaan, Nicholas M.; Kordower, Jeffrey H.

    2012-01-01

    Ageing is the greatest risk factor for the development of Parkinson’s disease. However, the current dogma holds that cellular mechanisms that are associated with ageing of midbrain dopamine neurons and those that are related to dopamine neuron degeneration in Parkinson’s disease are unrelated. We propose, based on evidence from studies of non-human primates, that normal ageing and the degeneration of dopamine neurons in Parkinson’s disease are linked by the same cellular mechanisms and, therefore, that markers of cellular risk factors accumulate with age in a pattern that mimics the pattern of degeneration observed in Parkinson’s disease. We contend that ageing induces a pre-parkinsonian state, and that the cellular mechanisms of dopamine neuron demise during normal ageing are accelerated or exaggerated in Parkinson’s disease through a combination of genetic and environmental factors. PMID:21587290

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

    PubMed Central

    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.

    2015-01-01

    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 to 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 5-fold 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 by simply tuning their spherical dimensions. PMID:25985456

  13. Interaction of non-human primate complement and antibodies with hypermucoviscous Klebsiella pneumoniae.

    PubMed

    Soto, Esteban; Marchi, Sylvia; Beierschmitt, Amy; Kearney, Michael; Francis, Stewart; VanNess, Kimberly; Vandenplas, Michel; Thrall, MaryAnna; Palmour, Roberta

    2016-01-01

    Emergent hypermucoviscosity (HMV) phenotypes of Klebsiella pneumoniae have been associated with increased invasiveness and pathogenicity in primates. In this study, we investigated the interaction of African green monkeys (AGM) (Chlorocebus aethiops sabaeus) complement and antibody with HMV and non-HMV isolates as in vitro models of primate infection. Significantly greater survival of HMV isolates was evident after incubation in normal serum or whole blood (p < 0.05) of AGM donors when compared to non-HMV strains. Greater survival of HMV strains (p < 0.05) was found after incubation in whole blood and serum from seropositive donors when compared to seronegative donor samples. Additionally, significantly greater amounts of K. pneumoniae were phagocytozed by AGM leukocytes when complement was active (p < 0.05), but no difference in uptake was observed when serum from seropositive or seronegative animals was used in challenged cells utilizing flow cytometry. Results demonstrate that interaction of cellular and humoral immune elements play a role in the in vitro killing of K. pneumoniae, particularly HMV isolates. Neither AGM serum, nor washed whole blood effectively killed HMV isolates; however, assays using heparinized whole blood of seronegative donors significantly reduced viability of HMV and non-HMV strains. The lack of bacterial killing observed in seropositive donors treatments could be at least partially associated with low IgG2 present in these animals. A better understanding of the pathogenesis of klebsiellosis in primates and host immune response is necessary to identify surface molecules that can induce both opsonizing and bactericidal antibody facilitating killing of Klebsiella, and the development of vaccines in human and animals. PMID:26951091

  14. 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. PMID:26367124

  15. Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates.

    PubMed

    Nixon, Andrew E; Chen, Jie; Sexton, Daniel J; Muruganandam, Arumugam; Bitonti, Alan J; Dumont, Jennifer; Viswanathan, Malini; Martik, Diana; Wassaf, Dina; Mezo, Adam; Wood, Clive R; Biedenkapp, Joseph C; TenHoor, Chris

    2015-01-01

    The therapeutic management of antibody-mediated autoimmune disease typically involves immunosuppressant and immunomodulatory strategies. However, perturbing the fundamental role of the neonatal Fc receptor (FcRn) in salvaging IgG from lysosomal degradation provides a novel approach - depleting the body of pathogenic immunoglobulin by preventing IgG binding to FcRn and thereby increasing the rate of IgG catabolism. Herein, we describe the discovery and preclinical evaluation of fully human monoclonal IgG antibody inhibitors of FcRn. Using phage display, we identified several potent inhibitors of human-FcRn in which binding to FcRn is pH-independent, with over 1000-fold higher affinity for human-FcRn than human IgG-Fc at pH 7.4. FcRn antagonism in vivo using a human-FcRn knock-in transgenic mouse model caused enhanced catabolism of exogenously administered human IgG. In non-human primates, we observed reductions in endogenous circulating IgG of >60% with no changes in albumin, IgM, or IgA. FcRn antagonism did not disrupt the ability of non-human primates to mount IgM/IgG primary and secondary immune responses. Interestingly, the therapeutic anti-FcRn antibodies had a short serum half-life but caused a prolonged reduction in IgG levels. This may be explained by the high affinity of the antibodies to FcRn at both acidic and neutral pH. These results provide important preclinical proof of concept data in support of FcRn antagonism as a novel approach to the treatment of antibody-mediated autoimmune diseases. PMID:25954273

  16. MAP2 Immunostaining in Thick Sections for Early Ischemic Stroke Infarct Volume in Non-Human Primate Brain

    PubMed Central

    Kharlamov, Alexander; LaVerde, George C.; Nemoto, Edwin M.; Jungreis, Charles A.; Yushmanov, Victor E.; Jones, Stephen C.; Boada, Fernando E.

    2009-01-01

    The delineation of early infarction in large gyrencephalic brain cannot be accomplished with triphenyl-tetrazolium chloride (TTC) due to its limitations in the early phase, nor can it be identified with microtubule-associated protein 2 (MAP2) immunohistochemistry, due to the fragility of large thin sections. We hypothesize that MAP2 immunostaining of thick whole-brain sections can accurately identify early ischemia in the entire monkey brain. Using ischemic brains of one rat and three monkeys, a thick-section MAP2 immunostaining protocol was developed to outline the infarct region over the entire non-human primate brain. Comparison of adjacent thick and thin sections in a rat brain indicated complete correspondence between ischemic regions (100.4 mm3 ± 1.2%, n = 7, p = 0.44). Thick sections in monkey brain possessed the increased structural stability necessary for the extensive MAP2 immunostaining procedure permitting quantification of the ischemic region as a percent of total monkey brain, giving infarct volumes of 11.4, 16.3, and 19.0% of total brain. Stacked 2D images of the intact thick brain tissue sections provided a 3D representation for comparison to MRI images. The infarct volume of 16.1 cm3 from the MAP2 sections registered with MRI images agreed well with the volume calculated directly from the stained sections of 16.6 cm3. Thick brain tissue section MAP2 immunostaining provides a new method for determining infarct volume over the entire brain at early time points in a non-human primate model of ischemic stroke. PMID:19540877

  17. 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

  18. 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

  19. Appetite Enhancement and Weight Gain by Peripheral Administration of TrkB Agonists in Non-Human Primates

    PubMed Central

    Lin, John C.; Tsao, David; Barras, Paul; Bastarrachea, Raul A.; Boyd, Bob; Chou, Joyce; Rosete, Rodnie; Long, Hua; Forgie, Alison; Abdiche, Yasmina; Dilley, Jeanette; Stratton, Jennifer; Garcia, Carlos; Sloane, David L.; Comuzzie, Anthony G.; Rosenthal, Arnon

    2008-01-01

    Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity. PMID:18382675

  20. 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. PMID:24560030

  1. Reference in human and non-human primate communication: What does it take to refer?

    PubMed

    Sievers, Christine; Gruber, Thibaud

    2016-07-01

    The concept of functional reference has been used to isolate potentially referential vocal signals in animal communication. However, its relatedness to the phenomenon of reference in human language has recently been brought into question. While some researchers have suggested abandoning the concept of functional reference altogether, others advocate a revision of its definition to include contextual cues that play a role in signal production and perception. Empirical and theoretical work on functional reference has also put much emphasis on how the receiver understands the referential signal. However, reference, as defined in the linguistic literature, is an action of the producer, and therefore, any definition describing reference in non-human animals must also focus on the producer. To successfully determine whether a signal is used to refer, we suggest an approach from the field of pragmatics, taking a closer look at specific situations of signal production, specifically at the factors that influence the production of a signal by an individual. We define the concept of signaller's reference to identify intentional acts of reference produced by a signaller independently of the communicative modality, and illustrate it with a case study of the hoo vocalizations produced by wild chimpanzees during travel. This novel framework introduces an intentional approach to referentiality. It may therefore permit a closer comparison of human and non-human animal referential behaviour and underlying cognitive processes, allowing us to identify what may have emerged solely in the human lineage. PMID:26971953

  2. Evidence for coordinated functional activity within the extended amygdala of non-human and human primates

    PubMed Central

    Oler, Jonathan A.; Birn, Rasmus M.; Patriat, Rémi; Fox, Andrew S.; Shelton, Steven E.; Burghy, Cory A.; Stodola, Diane E.; Essex, Marilyn J.; Davidson, Richard J.; Kalin, Ned H.

    2012-01-01

    Neuroanatomists posit that the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST) comprise two major nodes of a macrostructural forebrain entity termed the extended amygdala. The extended amygdala is thought to play a critical role in adaptive motivational behavior and is implicated in the pathophysiology of maladaptive fear and anxiety. Resting functional connectivity of the Ce was examined in 107 young anesthetized rhesus monkeys and 105 young humans using standard resting-state functional magnetic resonance imaging (fMRI) methods to assess temporal correlations across the brain. The data expand the neuroanatomical concept of the extended amygdala by finding, in both species, highly significant functional coupling between the Ce and the BST. These results support the use of in vivo functional imaging methods in nonhuman and human primates to probe the functional anatomy of major brain networks such as the extended amygdala. PMID:22465841

  3. 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

  4. Inducible nitric oxide synthase (iNOS) regulatory region variation in non-human primates

    PubMed Central

    Roodgar, Morteza; Ross, Cody T.; Kenyon, Nicholas J.; Marcelino, Gretchen; Smith, David Glenn

    2015-01-01

    Inducible nitric oxide synthase (iNOS) is an enzyme that plays a key role in intracellular immune response against respiratory infections. Since various species of nonhuman primates exhibit different levels of susceptibility to infectious respiratory diseases, and since variation in regulatory regions of genes is thought to play a key role in expression levels of genes, two candidate regulatory regions of iNOS were mapped, sequenced, and compared across five species of nonhuman primates: African green monkeys (chlorocebus sabeus), pig-tailed macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), Indian rhesus macaques (Macaca mulatta), and Chinese rhesus macaques (M. mulatta). In addition, we conducted an in silico analysis of the transcription factor binding sites associated with genetic variation in these two candidate regulatory regions across species. We found that only one of the two candidate regions showed strong evidence of involvement in iNOS regulation. Specifically, we found evidence of 13 conserved binding site candidates linked to iNOS regulation: AP-1, C/EBPB, CREB, GATA-1, GATA-3, NF-AT, NF-AT5, NF-κB, KLF4, Oct-1, PEA3, SMAD3, and TCF11. Additionally, we found evidence of interspecies variation in binding sites for several regulatory elements linked to iNOS (GATA-3, GATA-4, KLF6, SRF, STAT-1, STAT-3, OLF-1 and HIF-1) across species, especially in African green monkeys relative to other species. Given the key role of iNOS in respiratory immune response, the findings of this study might help guide the direction of future studies aimed to uncover the molecular mechanisms underlying the increased susceptibility of African green monkeys to several viral and bacterial respiratory infections. PMID:25675838

  5. Molecular identification and characterization of Mycobacterium avium subspecies paratuberculosis in free living non-human primate (Rhesus macaques) from North India.

    PubMed

    Singh, S V; Singh, A V; Singh, P K; Kumar, A; Singh, B

    2011-05-01

    In recent years, Mycobacterium avium subspecies paratuberculosis (MAP) has emerged as major animal pathogen with significant zoonotic concerns, worldwide. MAP infection is endemic in domestic and wild ruminant population in India. However, information on MAP infection in free ranging animal species and non human primates is limited. Present study aimed to estimate the status of MAP infection in free living Rhesus macaques suffering with multiple clinical conditions (coughing and loose stool). A total of 25 stool samples were collected from six colonies of Rhesus macaques from Mathura region (North India) and screened for the presence of MAP, using microscopic examination and IS900 PCR, directly from stool samples. PCR positive DNA samples were further genotyped using IS1311 PCR-restriction enzyme analysis. Of the 25 stool samples, 10 (40.0%) and 2 (8.0%) were positive for MAP using microscopic examination and direct IS900 PCR, respectively. IS900 PCR positive DNA samples were genotyped as 'Indian Bison type', which is a major MAP genotype infecting domestic and wild ruminant species and human beings in India. Prevalence of MAP in Rhesus macaques (Indian monkeys) was moderately high and confirmed interspecies sharing of MAP between domestic livestock and non-human primates. Presence of MAP in non-human primates, support the etiological role of MAP in inflammatory bowel disease patients. Indian monkeys may serve as model for understanding the role of non-human primates in sustenance, transmission and pathogenesis of MAP infection. PMID:21255839

  6. Temporal and Spatial Categorization in Human and Non-Human Primates

    PubMed Central

    Mendez, Juan Carlos; Prado, Luis; Mendoza, German; Merchant, Hugo

    2011-01-01

    It has been proposed that a functional overlap exists in the brain for temporal and spatial information processing. To test this, we designed two relative categorization tasks in which human subjects and a Rhesus monkey had to assign time intervals or distances to a “short” or “long” category according to varying prototypes. The performance of both species was analyzed using psychometric techniques that showed that they may have similar perceptual, memory, and/or decision mechanisms, specially for the estimation of time intervals. We also did a correlation analysis with human subjects’ psychometric thresholds and the results imply that indeed, temporal and spatial information categorization share neural substrates. However, not all of the tested distances and intervals correlated with each other, suggesting the existence of sub-circuits that process restricted ranges of distances and intervals. A different analysis was done on the monkey data, in which the influence of the previous categorical prototypes was measured on the task currently being performed. Again, we found a significant interaction between previous and current interval and distance categorization. Overall, the present paper points toward common or at least partially overlapped neural circuits for temporal and spatial categorization in primates. PMID:21927599

  7. Baby on board: olfactory cues indicate pregnancy and fetal sex in a non-human primate

    PubMed Central

    Crawford, Jeremy Chase; Drea, Christine M.

    2015-01-01

    Olfactory cues play an integral, albeit underappreciated, role in mediating vertebrate social and reproductive behaviour. These cues fluctuate with the signaller's hormonal condition, coincident with and informative about relevant aspects of its reproductive state, such as pubertal onset, change in season and, in females, timing of ovulation. Although pregnancy dramatically alters a female's endocrine profiles, which can be further influenced by fetal sex, the relationship between gestation and olfactory cues is poorly understood. We therefore examined the effects of pregnancy and fetal sex on volatile genital secretions in the ring-tailed lemur (Lemur catta), a strepsirrhine primate possessing complex olfactory mechanisms of reproductive signalling. While pregnant, dams altered and dampened their expression of volatile chemicals, with compound richness being particularly reduced in dams bearing sons. These changes were comparable in magnitude with other, published chemical differences among lemurs that are salient to conspecifics. Such olfactory ‘signatures’ of pregnancy may help guide social interactions, potentially promoting mother–infant recognition, reducing intragroup conflict or counteracting behavioural mechanisms of paternity confusion; cues that also advertise fetal sex may additionally facilitate differential sex allocation. PMID:25716086

  8. Baby on board: olfactory cues indicate pregnancy and fetal sex in a non-human primate.

    PubMed

    Crawford, Jeremy Chase; Drea, Christine M

    2015-02-01

    Olfactory cues play an integral, albeit underappreciated, role in mediating vertebrate social and reproductive behaviour. These cues fluctuate with the signaller's hormonal condition, coincident with and informative about relevant aspects of its reproductive state, such as pubertal onset, change in season and, in females, timing of ovulation. Although pregnancy dramatically alters a female's endocrine profiles, which can be further influenced by fetal sex, the relationship between gestation and olfactory cues is poorly understood. We therefore examined the effects of pregnancy and fetal sex on volatile genital secretions in the ring-tailed lemur (Lemur catta), a strepsirrhine primate possessing complex olfactory mechanisms of reproductive signalling. While pregnant, dams altered and dampened their expression of volatile chemicals, with compound richness being particularly reduced in dams bearing sons. These changes were comparable in magnitude with other, published chemical differences among lemurs that are salient to conspecifics. Such olfactory 'signatures' of pregnancy may help guide social interactions, potentially promoting mother-infant recognition, reducing intragroup conflict or counteracting behavioural mechanisms of paternity confusion; cues that also advertise fetal sex may additionally facilitate differential sex allocation. PMID:25716086

  9. FUNCTIONAL RECOVERY FOLLOWING MOTOR CORTEX LESIONS IN NON-HUMAN PRIMATES: EXPERIMENTAL IMPLICATIONS FOR HUMAN STROKE PATIENTS

    PubMed Central

    Darling, Warren G.; Pizzimenti, Marc A.; Morecraft, Robert J.

    2013-01-01

    This review discusses selected classical works and contemporary research on recovery of contralesional fine hand motor function following lesions to motor areas of the cerebral cortex in non-human primates. Findings from both the classical literature and contemporary studies show that lesions of cortical motor areas induce paresis initially, but are followed by remarkable recovery of fine hand/digit motor function that depends on lesion size and post-lesion training. Indeed, in recent work where considerable quantification of fine digit function associated with grasping and manipulating small objects has been observed, very favorable recovery is possible with minimal forced use of the contralesional limb. Studies of the mechanisms underlying recovery have shown that following small lesions of the digit areas of primary motor cortex (M1), there is expansion of the digit motor representations into areas of M1 that did not produce digit movements prior to the lesion. However, after larger lesions involving the elbow, wrist and digit areas of M1, no such expansion of the motor representation was observed, suggesting that recovery was due to other cortical or subcortical areas taking over control of hand/digit movements. Recently, we showed that one possible mechanism of recovery after lesion to the arm areas of M1 and lateral premotor cortex is enhancement of corticospinal projections from the medially located supplementary motor area (M2) to spinal cord laminae containing neurons which have lost substantial input from the lateral motor areas and play a critical role in reaching and digit movements. Because human stroke and brain injury patients show variable, and usually poorer, recovery of hand motor function than that of nonhuman primates after motor cortex damage, we conclude with a discussion of implications of this work for further experimentation to improve recovery of hand function in human stroke patients. PMID:21960307

  10. Sleep deprivation impairs spatial retrieval but not spatial learning in the non-human primate grey mouse lemur.

    PubMed

    Rahman, Anisur; Languille, Solène; Lamberty, Yves; Babiloni, Claudio; Perret, Martine; Bordet, Regis; Blin, Olivier J; Jacob, Tom; Auffret, Alexandra; Schenker, Esther; Richardson, Jill; Pifferi, Fabien; Aujard, Fabienne

    2013-01-01

    A bulk of studies in rodents and humans suggest that sleep facilitates different phases of learning and memory process, while sleep deprivation (SD) impairs these processes. Here we tested the hypothesis that SD could alter spatial learning and memory processing in a non-human primate, the grey mouse lemur (Microcebus murinus), which is an interesting model of aging and Alzheimer's disease (AD). Two sets of experiments were performed. In a first set of experiments, we investigated the effects of SD on spatial learning and memory retrieval after one day of training in a circular platform task. Eleven male mouse lemurs aged between 2 to 3 years were tested in three different conditions: without SD as a baseline reference, 8 h of SD before the training and 8 h of SD before the testing. The SD was confirmed by electroencephalographic recordings. Results showed no effect of SD on learning when SD was applied before the training. When the SD was applied before the testing, it induced an increase of the amount of errors and of the latency prior to reach the target. In a second set of experiments, we tested the effect of 8 h of SD on spatial memory retrieval after 3 days of training. Twenty male mouse lemurs aged between 2 to 3 years were tested in this set of experiments. In this condition, the SD did not affect memory retrieval. This is the first study that documents the disruptive effects of the SD on spatial memory retrieval in this primate which may serve as a new validated challenge to investigate the effects of new compounds along physiological and pathological aging. PMID:23717620

  11. Generation of a universal CD4 memory T cell recall peptide effective in humans, mice and non-human primates.

    PubMed

    Fraser, Christopher C; Altreuter, David H; Ilyinskii, Petr; Pittet, Lynnelle; LaMothe, Robert A; Keegan, Mark; Johnston, Lloyd; Kishimoto, Takashi Kei

    2014-05-19

    CD4T cells play a key role in humoral immunity by providing help to B cells, enabling effective antibody class switching and affinity maturation. Some vaccines may generate a poor response due to a lack of effective MHC class II epitopes, resulting in ineffective helper T cell activation and recall and consequently poor humoral immunity. It may be beneficial to provide a CD4T cell helper peptide with a vaccine particularly in the case of a poorly immunogenic antigen. Such a T cell helper peptide must be promiscuous in its ability to bind a broad range of MHC class II alleles due to broad allelic variation in the human population. We designed a chimeric MHC class II peptide (TpD) with epitopes from tetanus toxoid and diphtheria toxoid, separated by an internal cathepsin cleavage site. TpD was capable of inducing a memory recall response in peripheral blood mononuclear cells from 20/20 human donors. T cells responding to TpD showed a central memory phenotype. Immunization of mice with a synthetic nicotine nanoparticle vaccine containing TpD showed that the peptide was required for robust antibody production and resulted in a long term CD4 memory T cell recall response. As a pre-clinical model two non-human primate species, rhesus macaques and cynomolgus monkeys, were immunized with a nicotine nanoparticle vaccine and evaluated for an anti-nicotine antibody response and TpD specific memory T cells. We found that 4/4 rhesus monkeys had both sustained antibody production and TpD memory T cells for the duration of the experiment (119 days). In addition 30/30 cynomolgus monkeys dosed with nicotine vaccine nanoparticles showed dose-dependent antibody generation and T cell recall response compared to saline injected controls. In summary we have developed a potent universal memory T cell helper peptide (TpD) that is active in vitro in human PBMCs and in vivo in mice and non-human primates. PMID:24583006

  12. Life stage differences in mammary gland gene expression profile in non-human primates

    PubMed Central

    Sielker, Sonja; Wood, Charles E.; Register, Thomas C.; Lees, Cynthia J.; Dewi, Fitriya N.; Williams, J. Koudy; Wagner, Janice D.; Stefenelli, Ulrich; Cline, J. Mark

    2013-01-01

    Breast cancer (BC) is the most common malignancy of women in the developed world. To better understand its pathogenesis, knowledge of normal breast development is crucial, as BC is the result of disregulation of physiologic processes. The aim of this study was to investigate the impact of reproductive life stages on the transcriptional profile of the mammary gland in a primate model. Comparative transcriptomic analyses were carried out using breast tissues from 28 female cynomolgus macaques (Macaca fascicularis) at the following life stages: prepubertal (n = 5), adolescent (n = 4), adult luteal (n = 5), pregnant (n = 6), lactating (n = 3), and postmenopausal (n = 5). Mammary gland RNA was hybridized to Affymetrix GeneChip® Rhesus Macaque Genome Arrays. Differential gene expression was analyzed using ANOVA and cluster analysis. Hierarchical cluster analysis revealed distinct separation of life stage groups. More than 2,225 differentially expressed mRNAs were identified. Gene families or pathways that changed across life stages included those related to estrogen and androgen (ESR1, PGR, TFF1, GREB1, AR, 17HSDB2, 17HSDB7, STS, HSD11B1, AKR1C4), prolactin (PRLR, ELF5, STAT5, CSN1S1), insulin-like growth factor signaling (IGF1, IGFBP1, IGFBP5), extracellular matrix (POSTN, TGFB1, COL5A2, COL12A1, FOXC1, LAMC1, PDG-FRA, TGFB2), and differentiation (CD24, CD29, CD44, CD61, ALDH1, BRCA1, FOXA1, POSTN, DICER1, LIG4, KLF4, NOTCH2, RIF1, BMPR1A, TGFB2). Pregnancy and lactation displayed distinct patterns of gene expression. ESR1 and IGF1 were significantly higher in the adolescent compared to the adult animals, whereas differentiation pathways were overrepresented in adult animals and pregnancy-associated life stages. Few individual genes were distinctly different in postmenopausal animals. Our data demonstrate characteristic patterns of gene expression during breast development. Several of the pathways activated during pubertal development have been implicated in cancer

  13. Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression.

    PubMed

    Unzu, C; Melero, I; Hervás-Stubbs, S; Sampedro, A; Mancheño, U; Morales-Kastresana, A; Serrano-Mendioroz, I; de Salamanca, R E; Benito, A; Fontanellas, A

    2015-11-01

    Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) of HDA only resulted in transient (≈14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS. PMID:26125605

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

    PubMed Central

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

    2015-01-01

    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. PMID:26496829

  15. Medical relevance of UK-funded non-human primate research published from January 1997 to July 2012

    PubMed Central

    2014-01-01

    In 2012, the Bateson Review of research using non-human primates (NHPs) recommended the commissioning of a working group to identify and follow-up the results of UK-funded NHP research of potential benefit for human health (Recommendation 4), but the Medical Research Council (MRC) has postponed implementation of the recommendation. Information on results and potential benefits of NHP research therefore remains unavailable. To fill this gap in knowledge, this study identified all published NHP research studies funded by the MRC, Wellcome Trust and Biotechnology and Biological Sciences Research Council (BBSRC) from January 1997 to July 2012 and assessed full texts for medical relevance. In total, 284 papers were identified, of which 51 (18%) involved invasive NHP research, compared to 176 (61%) which used NHP tissue and cell lines, indicating a shift in research emphasis from invasive whole animal to cell-based research. Of these studies, 98 (35%) were medically relevant, of which 22 had potential therapeutic or public health applications. The relatively low proportion of medical studies together with the small number of applied studies raises questions over the level of investment in medical research and the effectiveness of knowledge transfer from basic to applied research. Implementation of the Bateson Review’s Recommendation 4 would address these questions. PMID:24739383

  16. Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model.

    PubMed

    Obaldía, Nicanor; Dow, Geoffrey S; Gerena, Lucia; Kyle, Dennis; Otero, William; Mantel, Pierre-Yves; Baro, Nicholas; Daniels, Rachel; Mukherjee, Angana; Childs, Lauren M; Buckee, Caroline; Duraisingh, Manoj T; Volkman, Sarah K; Wirth, Dyann F; Marti, Matthias

    2016-01-01

    Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model. PMID:26880111

  17. The extent of chromosomal aberrations induced by chemotherapy in non-human primates depends on the schedule of administration.

    PubMed

    Rao, V Koneti; Knutsen, Turid; Ried, Thomas; Wangsa, Darawalee; Flynn, Bernard Mike; Langham, Gregory; Egorin, Merrill J; Cole, Diane; Balis, Frank; Steinberg, Seth M; Bates, Susan; Fojo, Tito

    2005-06-01

    We utilized a non-human primate model, the rhesus monkey (Macaca mulatta), to quantitate the extent of chromosomal damage in bone marrow cells following chemotherapy. Thiotepa, etoposide, and paclitaxel were chosen as the chemotherapy agents due to their distinct mechanisms of action. Chromosomal aberrations were quantitated using traditional Giemsa stain. We sought to evaluate the extent to which genotoxicity was dependent on the schedule of administration by giving chemotherapy as either a bolus or a 96 h continuous infusion. Neutropenia and areas under the concentration curve (AUCs) were monitored to ensure comparable cytotoxicity and dose administered. At least 100 metaphases were scored in each marrow sample by an investigator unaware of the treatment history of the animals. All three drugs produced a statistically significant higher percentage of abnormal metaphases following bolus chemotherapy (p<0.0001, p=0.0015 and p<0.0001 for thiotepa, etoposide and paclitaxel, respectively). We conclude that infusional administration of thiotepa, etoposide and paclitaxel is less genotoxic to normal bone marrow cells than is bolus administration. These results suggest infusional regimens may be considered where there are concerns about long-term genotoxic sequelae, including secondary cancer, teratogenicity, or possibly the development of drug resistance. We believe this approach provides a reproducible model in which drugs and eventually, regimens can be compared. PMID:15927870

  18. 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. PMID:25920329

  19. THE NON-HUMAN PRIMATE AMYGDALA IS NECESSARY FOR THE ACQUISITION BUT NOT THE RETENTION OF FEAR-POTENTIATED STARTLE

    PubMed Central

    Antoniadis, Elena A.; Winslow, James T.; Davis, Michael; Amaral, David G.

    2009-01-01

    Background In a previous study (1), we found that rhesus monkeys prepared with bilateral lesions of the amygdala failed to acquire fear-potentiated startle to a visual cue. However, a second group of monkeys, that received the lesion after training, successfully demonstrated fear-potentiated startle learned prior to the lesion. Methods In the current experiment, the eight monkeys used in the second part of the original study (1), four of whom had bilateral amygdala lesions and their four controls, were trained using an auditory cue and tested in the fear-potentiated startle paradigm. This test was performed to determine whether they could acquire fear-potentiated startle to a new cue. Results Monkeys with essentially complete damage to the amygdala (based on histological analysis), who had retained and expressed fear-potentiated startle to a visual cue learned before the lesion (1), failed to acquire fear-potentiated startle to an auditory cue, when training occurred after the lesion. Conclusions The results suggest that while the non-human primate amygdala is essential for the initial acquisition of fear conditioning, it does not appear to be necessary for the memory and expression of conditioned fear. These findings are discussed in relation to a network of connections between the amygdala and the orbitofrontal cortex that may subserve different component processes of fear conditioning. PMID:18823878

  20. Medical relevance of UK-funded non-human primate research published from January 1997 to July 2012.

    PubMed

    Moore, Edward

    2014-04-16

    In 2012, the Bateson Review of research using non-human primates (NHPs) recommended the commissioning of a working group to identify and follow-up the results of UK-funded NHP research of potential benefit for human health (Recommendation 4), but the Medical Research Council (MRC) has postponed implementation of the recommendation. Information on results and potential benefits of NHP research therefore remains unavailable. To fill this gap in knowledge, this study identified all published NHP research studies funded by the MRC, Wellcome Trust and Biotechnology and Biological Sciences Research Council (BBSRC) from January 1997 to July 2012 and assessed full texts for medical relevance. In total, 284 papers were identified, of which 51 (18%) involved invasive NHP research, compared to 176 (61%) which used NHP tissue and cell lines, indicating a shift in research emphasis from invasive whole animal to cell-based research. Of these studies, 98 (35%) were medically relevant, of which 22 had potential therapeutic or public health applications. The relatively low proportion of medical studies together with the small number of applied studies raises questions over the level of investment in medical research and the effectiveness of knowledge transfer from basic to applied research. Implementation of the Bateson Review's Recommendation 4 would address these questions. PMID:24739383

  1. 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. PMID:23563364

  2. 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.

  3. Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model.

    PubMed

    Weber, Benedikt; Dijkman, Petra E; Scherman, Jacques; Sanders, Bart; Emmert, Maximilian Y; Grünenfelder, Jürg; Verbeek, Renier; Bracher, Mona; Black, Melanie; Franz, Thomas; Kortsmit, Jeroen; Modregger, Peter; Peter, Silvia; Stampanoni, Marco; Robert, Jérôme; Kehl, Debora; van Doeselaar, Marina; Schweiger, Martin; Brokopp, Chad E; Wälchli, Thomas; Falk, Volkmar; Zilla, Peter; Driessen-Mol, Anita; Baaijens, Frank P T; Hoerstrup, Simon P

    2013-10-01

    Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs. PMID:23810254

  4. Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model

    PubMed Central

    Obaldía III, Nicanor; Dow, Geoffrey S.; Gerena, Lucia; Kyle, Dennis; Otero, William; Mantel, Pierre-Yves; Baro, Nicholas; Daniels, Rachel; Mukherjee, Angana; Childs, Lauren M.; Buckee, Caroline; Duraisingh, Manoj T.; Volkman, Sarah K.; Wirth, Dyann F.; Marti, Matthias

    2016-01-01

    Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model. PMID:26880111

  5. GSK3β Inhibition Promotes Efficient Myeloid and Lymphoid Hematopoiesis from Non-human Primate-Induced Pluripotent Stem Cells

    PubMed Central

    D'Souza, Saritha S.; Maufort, John; Kumar, Akhilesh; Zhang, Jiuchun; Smuga-Otto, Kimberley; Thomson, James A.; Slukvin, Igor I.

    2016-01-01

    Summary Advances in the scalable production of blood cells from induced pluripotent stem cells (iPSCs) open prospects for the clinical translation of de novo generated blood products, and evoke the need for preclinical evaluation of their efficacy, safety, and immunogenicity in large animal models. Due to substantial similarities with humans, the outcomes of cellular therapies in non-human primate (NHP) models can be readily extrapolated to a clinical setting. However, the use of this model is hampered by relatively low efficiency of blood generation and lack of lymphoid potential in NHP-iPSC differentiation cultures. Here, we generated transgene-free iPSCs from different NHP species and showed the efficient induction of mesoderm, myeloid, and lymphoid cells from these iPSCs using a GSK3β inhibitor. Overall, our studies enable scalable production of hematopoietic progenitors from NHP-iPSCs, and lay the foundation for preclinical testing of iPSC-based therapies for blood and immune system diseases in an NHP model. PMID:26805448

  6. The Temporal Dynamics of Regularity Extraction in Non-Human Primates.

    PubMed

    Minier, Laure; Fagot, Joël; Rey, Arnaud

    2016-05-01

    Extracting the regularities of our environment is one of our core cognitive abilities. To study the fine-grained dynamics of the extraction of embedded regularities, a method combining the advantages of the artificial language paradigm (Saffran, Aslin, & Newport, ) and the serial response time task (Nissen & Bullemer, ) was used with a group of Guinea baboons (Papio papio) in a new automatic experimental device (Fagot & Bonté, ). After a series of random trials, monkeys were exposed to language-like patterns. We found that the extraction of embedded patterns positioned at the end of larger patterns was faster than the extraction of initial embedded patterns. This result suggests that there is a learning advantage for the final element of a sequence that benefits from the contextual information provided by previous elements. PMID:26303229

  7. Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates

    PubMed Central

    Verina, Tatyana; Kiihl, Samara F; Schneider, Jay S; Guilarte, Tomás R

    2011-01-01

    Chronic manganese (Mn) exposure produces neurological deficits including a form of parkinsonism that is different from Parkinson's disease (PD). In chronic Mn exposure, dopamine neurons in the substantia nigra (SN) do not degenerate but they appear to be dysfunctional. Further, previous studies have suggested that the substantia nigra pars reticulata (SNr) is affected by Mn. In the present study, we investigated whether chronic Mn exposure induces microglia activation in the substantia nigra pars compacta (SNc) and SNr in Cynomolgus macaques. Animals were exposed to different weekly doses of Mn (3.3–5.0, 5.0-6.7, 8.3-10 mg Mn/kg body weight) and microglia were examined in the substantia nigra using LN3 immunohistochemistry. We observed that in control animals, LN3 labeled microglia were characterized by a resting phenotype. However, in Mn-treated animals, microglia increased in number and displayed reactive changes with increasing Mn exposure. This effect was more prominent in the SNr than in the SNc. In the SNr of animals administered the highest Mn dose, microglia activation was the most advanced and included dystrophic changes. Reactive microglia expressed increased iNOS, L-ferritin, and intracellular ferric iron which were particularly prominent in dystrophic compartments. Our observations indicate that moderate Mn exposure produces structural changes on microglia, which may have significant consequences on their function. PMID:21112353

  8. Effects of Chronic Manganese Exposure on Attention and Working Memory in Non-Human Primates

    PubMed Central

    Schneider, J.S.; Williams, C.; Ault, M.; Guilarte, T.R.

    2015-01-01

    Manganese (Mn) is essential for a variety of physiological processes, but at elevated levels, can be neurotoxic. While cognitive dysfunction has been recently appreciated to occur as a result of chronic Mn exposures, it is still unclear as to which cognitive domains are most susceptible to disruption by Mn exposure. We previously described early appearing Mn-induced changes in performance on a paired associate learning task in monkeys chronically exposed to Mn and suggested that performance of this task might be a sensitive tool for detecting cognitive dysfunction resulting from Mn exposure. As chronic Mn exposure has been suggested to be associated with attention, working memory and executive function deficits, the present study was conducted to assess the extent to which detrimental effects of chronic Mn exposure could be detected using tasks specifically designed to preferentially assess attention, working memory, and executive function. Six cynomolgus monkeys received Mn exposure over an approximate 12 month period and three served as control animals. All animals were trained to perform a self-ordered spatial search (SOSS) task and a five choice serial reaction time (5-CSRT) task. Deficits in performance of the SOSS task began to appear by the fourth month of Mn exposure but only became consistently significantly impaired beginning at the ninth month of Mn exposure. Performance on the 5-CSRT became significantly affected by the third month of Mn exposure. These data suggest that in addition to the paired associate learning task, cognitive processing speed (as measured by the 5-CSRT) may be a sensitive measure of Mn toxicity and that brain circuits involved in performance of the SOSS task may be somewhat less sensitive to disruption by chronic Mn exposure. PMID:25917687

  9. Insights into the epidemiology and genetic make-up of Oesophagostomum bifurcum from human and non-human primates using molecular tools.

    PubMed

    Gasser, R B; de Gruijter, J M; Polderman, A M

    2006-04-01

    The nodule worm Oesophagostomum bifurcum (Nematoda: Strongylida) is a parasite of major human health importance predominantly in northern Togo and Ghana. Currently, it is estimated that 0.25 million people are infected with this nematode, and at least 1 million people are at risk of infection. Infection with this parasite causes significant disease as a consequence of encysted larvae in the wall of the large intestine. In spite of the health problems caused by O. bifurcum, there have been significant gaps in the knowledge of the biology, transmission and population genetics of the parasite. This review provides an account of some recent insights into the epidemiology and genetics of the parasite from human and non-human primate hosts in specific regions of Africa using molecular tools. Recent research findings are discussed mainly in relation to non-human primates being reservoirs of infection, and the consequences for the prevention and control of oesophagostomiasis in humans are briefly discussed. PMID:16332292

  10. Hippocampal CA1 cell loss in a non-human primate model of transient global ischemia: a pilot study.

    PubMed

    Hara, Koichi; Yasuhara, Takao; Matsukawa, Noriyuki; Maki, Mina; Masuda, Tadashi; Yu, Guolong; Xu, Lin; Tambrallo, Laura; Rodriguez, Nancy A; Stern, David M; Kawase, Takeshi; Yamashima, Tetsumori; Buccafusco, Jerry J; Hess, David C; Borlongan, Cesario V

    2007-09-14

    We exposed adult Rhesus (Macaca mulatta) to a transient global ischemia, which was induced by clipping the innominate and subclavian arteries that originated from the aortic arch. NHP1 received 20-min, while NHP2 and NHP3, were exposed to a 15-min transient global ischemia and were euthanized at day 1 (NHP1), day 5 (NHP2) or day 30 (NHP3) after ischemia, respectively. NHP1 displayed severe paralysis and rigidity, and intermittent convulsions over the next 24 h. Although histological examination of the brain revealed no detectable gross brain damage (i.e., swelling) and only minimal cell loss in the hippocampus, the acute survival time after surgery likely prevented the cerebral ischemia to fully develop and to be morphologically manifested. Nonetheless, the 20-min ischemia might have been too severe and caused a systemic multiple organ collapse that produced the abnormal behavioral symptoms. On the other hand, NHP2 and NHP3 which received 15-min ischemia only exhibited minor hindlimb paralysis. Indeed, by 48 h after ischemia, both animals appeared fully recovered with only fine motor deficits. Immunohistochemical examination revealed that NHP2 and 3, but not NHP1, had a marked neuronal cell loss in the hippocampal region, specifically the cornu Ammonis (CA1) region. The cell loss in these two ischemic NHP hippocampi was further confirmed by direct comparison with a normal Rhesus brain. These findings replicate the brain pathology seen in Japanese macaques exposed to the same ischemia model [T. Tsukada, M. Watanabe, T. Yamashima, Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus, J. Neurochem. 79 (2001) 1196-1206; T. Yamashima, Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates, Prog. Neurobiol. 62 (2000) 273-295; T. Yamashima, Y. Kohda, K. Tsuchiya, T. Ueno, J. Yamashita, T. Yoshioka, E. Kominami, Inhibition of ischemic hippocampal neuronal death in primates with

  11. A silicon based implantable microelectrode array for electrophysiological and dopamine recording from cortex to striatum in the non-human primate brain.

    PubMed

    Zhang, Song; Song, Yilin; Wang, Mixia; Zhang, Zhiming; Fan, Xinyi; Song, Xianteng; Zhuang, Ping; Yue, Feng; Chan, Piu; Cai, Xinxia

    2016-11-15

    Dual-mode, multielectrode recordings have become routine in rodent neuroscience research and have recently been adapted to the non-human primate. However, robust and reliable application of acute, multielectrode recording methods in monkeys especially for deep brain nucleus research remains a challenge. In this paper, We described a low cost silicon based 16-site implantable microelectrode array (MEA) chip fabricated by standard lithography technology for in vivo test. The array was 25mm long and designed to use in non-human primate models, for electrophysiological and electrochemical recording. We presented a detailed protocol for array fabrication, then showed that the device can record Spikes, LFPs and dopamine (DA) variation continuously from cortex to striatum in an esthetized monkey. Though our experiment, high-quality electrophysiological signals were obtained from the animal. Across any given microelectrode, spike amplitudes ranged from 70 to 300μV peak to peak, with a mean signal-to-noise ratio of better than 5:1. Calibration results showed the MEA probe had high sensitivity and good selectivity for DA. The DA concentration changed from 42.8 to 481.6μM when the MEA probe inserted from cortex into deep brain nucleus of striatum, which reflected the inhomogeneous distribution of DA in brains. Compared with existing methods allowing single mode (electrophysiology or electrochemistry) recording. This system is designed explicitly for dual-mode recording to meet the challenges of recording in non-human primates. PMID:27155116

  12. On the pursuit of the brain network for proto-syntactic learning in non-human primates: conceptual issues and neurobiological hypotheses

    PubMed Central

    Petkov, Christopher I.; Wilson, Benjamin

    2012-01-01

    Songbirds have become impressive neurobiological models for aspects of human verbal communication because they learn to sequence their song elements, analogous, in some ways, to how humans learn to produce spoken sequences with syntactic structure. However, mammals such as non-human primates are considered to be at best limited-vocal learners and not able to sequence their vocalizations, although some of these animals can learn certain ‘artificial grammar’ sequences. Thus, conceptual issues have slowed the progress in exploring potential neurobiological homologues to language-related processes in species that are taxonomically closely related to humans. We consider some of the conceptual issues impeding a pursuit of, as we define them, ‘proto-syntactic’ capabilities and their neuronal substrates in non-human animals. We also discuss ways to better bridge comparative behavioural and neurobiological data between humans and other animals. Finally, we propose guiding neurobiological hypotheses with which we aim to facilitate the future testing of the level of correspondence between the human brain network for syntactic-learning and related neurobiological networks present in other primates. Insights from the study of non-human primates and other mammals are likely to complement those being obtained in birds to further our knowledge of the human language-related network at the cellular level. PMID:22688642

  13. 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. PMID:25754762

  14. 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. PMID:26072016

  15. 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

  16. Non-human primate skull effects on the cavitation detection threshold of FUS-induced blood-brain barrier opening

    NASA Astrophysics Data System (ADS)

    Wu, Shih-Ying; Tung, Yao-Sheng; Marquet, Fabrice; Chen, Cherry C.; Konofagou, Elisa E.

    2012-11-01

    Microbubble (MB)-assisted focused ultrasound is a promising technique for delivering drugs to the brain by noninvasively and transiently opening the blood-brain barrier (BBB), and monitoring BBB opening using passive cavitation detection (PCD) is critical in detecting its occurrence, extent as well as assessing its mechanism. One of the main obstacles in achieving those objectives in large animals is the transcranial attenuation. To study the effects, the cavitation response through the in-vitro non-human primate (NHP) skull was investigated. In-house manufactured lipid-shelled MB (medium diameter: 4-5 um) were injected into a 4-mm channel of a phantom below a degassed monkey skull. A hydrophone confocally aligned with the FUS transducer served as PCD during sonication (frequency: 0.50 MHz, peak rarefactional pressures: 0.05-0.60 MPa, pulse length: 100 cycles, PRF: 10 Hz, duration: 2 s) for four cases: water without skull, water with skull, MB without skull and MB with skull. A 5.1-MHz linear-array transducer was also used to monitor the MB disruption. The frequency spectra, spectrograms, stable cavitation dose (SCD) and inertial cavitation dose (ICD) were quantified. Results showed that the onset of stable cavitation and inertial cavitation in the experiments occurred at 50 kPa, and was detectable throught the NHP skull since the both the detection thresholds for stable cavitation and inertial cavitation remained unchanged compared to the non-skull case, and the SCD and ICD acquired transcranially may not adequately represent the true extent of stable and inertial cavitation due to the skull attenuation.

  17. Engineering an Endothelialized Vascular Graft: A Rational Approach to Study Design in a Non-Human Primate Model

    PubMed Central

    Anderson, Deirdre E. J.; Glynn, Jeremy J.; Song, Howard K.; Hinds, Monica T.

    2014-01-01

    After many years of research, small diameter, synthetic vascular grafts still lack the necessary biologic integration to perform ideally in clinical settings. Endothelialization of vascular grafts has the potential to improve synthetic graft function, and endothelial outgrowth cells (EOCs) are a promising autologous cell source. Yet no work has established the link between endothelial cell functions and outcomes of implanted endothelialized grafts. This work utilized steady flow, oscillatory flow, and tumor necrosis factor stimulation to alter EOC phenotype and enable the formulation of a model to predict endothelialized graft performance. To accomplish this, EOC in vitro expression of coagulation and inflammatory markers was quantified. In parallel, in non-human primate (baboon) models, the platelet and fibrinogen accumulation on endothelialized grafts were quantified in an ex vivo shunt, or the tissue ingrowth on implanted grafts were characterized after 1mth. Oscillatory flow stimulation of EOCs increased in vitro coagulation markers and ex vivo platelet accumulation. Steady flow preconditioning did not affect platelet accumulation or intimal hyperplasia relative to static samples. To determine whether in vitro markers predict implant performance, a linear regression model of the in vitro data was fit to platelet accumulation data—correlating the markers with the thromboprotective performance of the EOCs. The model was tested against implant intimal hyperplasia data and found to correlate strongly with the parallel in vitro analyses. This research defines the effects of flow preconditioning on EOC regulation of coagulation in clinical vascular grafts through parallel in vitro, ex vivo, and in vivo analyses, and contributes to the translatability of in vitro tests to in vivo clinical graft performance. PMID:25526637

  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. 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. PMID:26670940

  20. 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.

  1. 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

  2. An inter-laboratory retrospective analysis of immunotoxicological endpoints in non-human primates: flow cytometry immunophenotyping.

    PubMed

    Krejsa, Cecile M; Neradilek, Moni Blazej; Polissar, Nayak L; Cox, Nick; Clark, Darcey; Cowan, Laine; Bussiere, Jeanine; Lebrec, Herve

    2013-01-01

    Non-human primates may be the only relevant species for pharmacology or toxicology studies of certain biologics, due to lack of activity in other species. Flow cytometry immunophenotyping is often included as a minimally invasive adjunct to standard toxicity testing. A retrospective inter-laboratory analysis was conducted to assess counts and variability of the main cell types monitored in toxicity studies, and to provide guidance for conduct and interpretation of immunophenotyping assessments in cynomolgus monkeys. Univariate and multivariate models were developed. Study design factors influencing cell counts and variability were identified and a power analysis was performed. Pre-study and on-study counts were generally similar; longitudinal analysis showed little drift in mean counts or within-animal variability over time. Within-animal variability was lower than inter-animal variability. Gender was associated with small but significant differences in mean counts and variability. Age was associated with significant differences in variability. Immunophenotype definitions were associated with significant differences in mean counts and within-animal variability for most cell types. Power analysis for groups of 6-8 animals showed that differences of ≈50% in counts of T-cells, T-cell subsets, and B-cells compared to pre-treatment values may be detected; for NK cells and monocytes, differences of ≈60-90% may be detected. This review yields some general points to consider for immunophenotyping studies, i.e. (a) analysis of log-transformed cell count data and comparisons using each animal as its own reference will improve ability to detect changes, (b) the magnitude of change detectable given study group size should be considered, (c) multiplication of sampling timepoints during a study seems unnecessary, (d) consideration should be given to using only one gender, when applicable, to increase power while minimizing animal usage, and (e) the choice of immunophenotype

  3. Multifocal electroretinogram (MFERG) evaluation of laser-induced secondary damage in the non-human primate (NHP)

    NASA Astrophysics Data System (ADS)

    Zwick, Harry; Stuck, Bruce E.; Akers, A.; Edsall, Peter; DiCarlo, Cheryl D.; Lund, David J.

    2005-04-01

    Laser induced retinal damage may involve primary injury to the central retina and secondary damage, including intraretinal scar formation (IRSF) retinal traction (RT) and retinal nerve fiber layer injury (RNFL). We have evaluated these laser induced retinal pathologies with MFERG in non-human primates (NHPs) with a Veris (4.9) MFERG system 103 Hexagons, centered on the macula with non-scaled arrays and in one NHP with a 2-frame/M-step sequence to assess long term exposure effects within the RNFL. Chemical restraint was achieved using Ketamine stability HCL (10 mg/kg IM) and Propofol (0.5 mg-1.2/Kg/min via syringe pump). Peribulbar eye blocks were performed using 2% lidocain or a mixture of 2% Lidocain/Marcain (monitored ocular motility was less than 40 microns in retinal space). Primary and secondary damage effects were induced with either q-switched single pulse Neodymium (1064 nm, 1.0 mJ) or Argon CW (10 to 1000 msec, 10-150 mW). MFERG demonstrated capability to detect primary and secondary induced retinal damage in both 1st and 2nd order kernels. Primary and secondary damage in the central retina was often suppressed in amplitude and with longer latencies relative to the MFERG norm. Preliminary investigations in one NHP with Primary and secondary RNFL damage at 9 to 14 months showed recovery with non-scaled array one frame / M-step sequence but demonstrated significant abnormalities for a two frame/ M-step sequence. Utilization of advanced Veris recording parameters involving spatial and temporal manipulation of the stimulus parameters can improve detection of functional deficits induced by focal laser retinal injury.

  4. 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

  5. Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model

    PubMed Central

    Ispas, Gabriela; Koul, Anil; Verbeeck, Johan; Sheehan, Jennifer; Sanders-Beer, Brigitte; Roymans, Dirk; Andries, Koen; Rouan, Marie-Claude; De Jonghe, Sandra; Bonfanti, Jean-François; Vanstockem, Marc; Simmen, Kenneth; Verloes, Rene

    2015-01-01

    Background The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI). Methods African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n=12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3:control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis. Findings TMC353121 showed a dose-dependent antiviral activity, varying from 1log10 reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 μg/mL) and was associated with a dose-dependent reduction in INFγ, IL6 and MIP1α. TMC353121 administered as CI for 16 days was generally well-tolerated. Conclusion TMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study. PMID:26010881

  6. Vitamin C Supplementation Ameliorates the Adverse Effects of Nicotine on Placental Hemodynamics and Histology in Non-Human Primates

    PubMed Central

    Lo, Jamie O.; Schabel, Matthias C.; Roberts, Victoria H.J.; Morgan, Terry K.; Rasanen, Juha P.; Kroenke, Christopher D.; Shoemaker, Ms. Sophie R.; Spindel, Eliot R.; Frias, Antonio E.

    2015-01-01

    Objective We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in non-human primates (NHP) and maternal Vitamin C supplementation attenuates these deleterious effects. However, nicotine’s effect on placental perfusion and development is not fully understood. This study utilizes non-invasive imaging techniques and histological analysis in a NHP model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development, but is ameliorated by Vitamin C. Study Design Time-mated macaques (n=27) in 4 treatment groups: control (n=5), nicotine only (n=4), Vitamin C only (n=9), and nicotine plus Vitamin C (n=9). Nicotine animals received 2mg/kg/day of nicotine bitartrate (~0.7mg/kg/day free nicotine levels in pregnant human smokers) from days 26–160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100 or 250mg/kg/day with or without nicotine. All underwent placental Dynamic Contrast-Enhanced MRI (DCE-MRI) at 135–140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow (cQuta) and placental volume blood flow (cQuv). Animals were delivered by cesarean section at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. Results Placental volume blood flow (cQuv) was significantly reduced in nicotine only animals compared with controls and nicotine plus Vitamin C groups (p=0.03). Maternal placental blood flow was not different between experimental groups by DCE-MRI ranging from 0.75–1.94 ml/ml/min (p=0.93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (p<0.05) and increased syncytiotrophoblast sprouting (p<0.001) in nicotine only animals, which was mitigated by Vitamin C. Conclusion Prenatal nicotine exposure significantly

  7. Effect of dietary fish oil supplementation on the exploratory activity, emotional status and spatial memory of the aged mouse lemur, a non-human primate.

    PubMed

    Languille, Solène; Aujard, Fabienne; Pifferi, Fabien

    2012-12-01

    The data are inconsistent about the ability of dietary omega-3 fatty acids to prevent age-associated cognitive decline. Indeed, most clinical trials have failed to demonstrate a protective effect of omega-3 fatty acids against cognitive decline, and methodological issues are still under debate. In contrast to human studies, experiments performed in adult rodents clearly indicate that omega-3 fatty acids supplement can improve behavioural and cognitive functions. The inconsistent observations between human and rodent studies highlight the importance of the use of non-human primate models. The aim of the present study was to address the impact of omega-3 fatty acids (given in the form of dietary fish oil) on exploratory activity, emotional status and spatial reference memory in the aged mouse lemur, a non-human primate. Aged animals fed fish oil exhibited decreased exploratory activity, as manifested by an increase in the latency to move and a reduced distance travelled in an open-field. The fish oil-supplemented animals exhibited no change in the anxiety level, but they were more reactive to go into the dark arms of a light/dark plus-maze. In addition, we found that fish oil supplementation did not significantly improve the spatial memory performance in the Barnes maze task. This study demonstrated for the first time that a fish oil diet initiated late in life specifically modifies the exploratory behaviour without improving the spatial memory of aged non-human primates. Omega-3 fatty acid supplementation may be effective when started early in life but less effective when started at later ages. PMID:22921374

  8. Hair cortisol levels track phylogenetic and age related differences in hypothalamic-pituitary-adrenal (HPA) axis activity in non-human primates.

    PubMed

    Fourie, Nicolaas H; Bernstein, Robin M

    2011-11-01

    Hair has been shown to archive a uniquely time averaged signal of endocrine activity, and holds attractive advantages for both laboratory and field research. Prior research has explored the potential of hair hormone analysis to examine hormone-behavior relationships. To date, no research has focused on the potential of the technique to investigate age-related changes or taxon differences in endocrine function. It is known that non-human primate infants of many taxa exhibit high cortisol levels after parturition, which rapidly decline with age. It has also been shown that hypercortisolism generally characterizes platyrrhine (New World monkey) endocrine function. These endocrine trends have been characterized using cortisol levels determined from serum, plasma, and feces. Here we test whether cortisol levels determined from hair recover similar phylogenetic and age related patterns in endocrine function in non-human primates. In order to test whether hair cortisol reflect infant hypercortisolism with significant age-related decline, hair cortisol levels are measured in samples from wild vervet monkeys (Chlorocebus aethiops) and captive Guinea baboons (Papio hamadryas papio), ranging in age from infants through juveniles. Further, in order to test whether platyrrhines exhibit significantly higher hair cortisol levels compared to strepsirrhines and catarrhines, and therefore faithfully recover similar signals as more traditionally used substrates (e.g. serum), hair cortisol levels are quantified in adult female hair samples collected from a broad range of non-human primate taxa. Results confirm that hair cortisol levels accurately reflect known phylogenetic and age related patterns of circulating cortisol levels. Therefore, these results suggest that hair may be an ideal hormone bearing substrate for research focused on the examination of population endocrine profiles, cross-sectional studies of endocrine function and taxon variation in hormone levels, as well as

  9. 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

  10. Hidden Population Structure and Cross-species Transmission of Whipworms (Trichuris sp.) in Humans and Non-human Primates in Uganda

    PubMed Central

    Ghai, Ria R.; Simons, Noah D.; Chapman, Colin A.; Omeja, Patrick A.; Davies, T. Jonathan; Ting, Nelson; Goldberg, Tony L.

    2014-01-01

    Background Whipworms (Trichuris sp.) are a globally distributed genus of parasitic helminths that infect a diversity of mammalian hosts. Molecular methods have successfully resolved porcine whipworm, Trichuris suis, from primate whipworm, T. trichiura. However, it remains unclear whether T. trichiura is a multi-host parasite capable of infecting a wide taxonomic breadth of primate hosts or a complex of host specific parasites that infect one or two closely related hosts. Methods and Findings We examined the phylogenetic structure of whipworms in a multi-species community of non-human primates and humans in Western Uganda, using both traditional microscopy and molecular methods. A newly developed nested polymerase chain reaction (PCR) method applied to non-invasively collected fecal samples detected Trichuris with 100% sensitivity and 97% specificity relative to microscopy. Infection rates varied significantly among host species, from 13.3% in chimpanzees (Pan troglodytes) to 88.9% in olive baboons (Papio anubis). Phylogenetic analyses based on nucleotide sequences of the Trichuris internal transcribed spacer regions 1 and 2 of ribosomal DNA revealed three co-circulating Trichuris groups. Notably, one group was detected only in humans, while another infected all screened host species, indicating that whipworms from this group are transmitted among wild primates and humans. Conclusions and Significance Our results suggest that the host range of Trichuris varies by taxonomic group, with some groups showing host specificity, and others showing host generality. In particular, one Trichuris taxon should be considered a multi-host pathogen that is capable of infecting wild primates and humans. This challenges past assumptions about the host specificity of this and similar helminth parasites and raises concerns about animal and human health. PMID:25340752

  11. A Single Dose Respiratory Recombinant Adenovirus-Based Vaccine Provides Long-Term Protection for Non-Human Primates from Lethal Ebola Infection

    PubMed Central

    2014-01-01

    As the Ebola outbreak in West Africa continues and cases appear in the United States and other countries, the need for long-lasting vaccines to preserve global health is imminent. Here, we evaluate the long-term efficacy of a respiratory and sublingual (SL) adenovirus-based vaccine in non-human primates in two phases. In the first, a single respiratory dose of 1.4 × 109 infectious virus particles (ivp)/kg of Ad-CAGoptZGP induced strong Ebola glycoprotein (GP) specific CD8+ and CD4+ T cell responses and Ebola GP-specific antibodies in systemic and mucosal compartments and was partially (67%) protective from challenge 62 days after immunization. The same dose given by the SL route induced Ebola GP-specific CD8+ T cell responses similar to that of intramuscular (IM) injection, however, the Ebola GP-specific antibody response was low. All primates succumbed to infection. Three primates were then given the vaccine in a formulation that improved the immune response to Ebola in rodents. Three primates were immunized with 2.0 × 1010 ivp/kg of vaccine by the SL route. Diverse populations of polyfunctional Ebola GP-specific CD4+ and CD8+ T cells and significant anti-Ebola GP antibodies were present in samples collected 150 days after respiratory immunization. The formulated vaccine was fully protective against challenge 21 weeks after immunization. While diverse populations of Ebola GP-specific CD4+ T cells were produced after SL immunization, antibodies were not neutralizing and the vaccine was unprotective. To our knowledge, this is the first time that durable protection from a single dose respiratory adenovirus-based Ebola vaccine has been demonstrated in primates. PMID:25363619

  12. A Single Dose Respiratory Recombinant Adenovirus-Based Vaccine Provides Long-Term Protection for Non-Human Primates from Lethal Ebola Infection.

    PubMed

    Choi, Jin Huk; Jonsson-Schmunk, Kristina; Qiu, Xiangguo; Shedlock, Devon J; Strong, Jim; Xu, Jason X; Michie, Kelly L; Audet, Jonathan; Fernando, Lisa; Myers, Mark J; Weiner, David; Bajrovic, Irnela; Tran, Lilian Q; Wong, Gary; Bello, Alexander; Kobinger, Gary P; Schafer, Stephen C; Croyle, Maria A

    2015-08-01

    As the Ebola outbreak in West Africa continues and cases appear in the United States and other countries, the need for long-lasting vaccines to preserve global health is imminent. Here, we evaluate the long-term efficacy of a respiratory and sublingual (SL) adenovirus-based vaccine in non-human primates in two phases. In the first, a single respiratory dose of 1.4×10(9) infectious virus particles (ivp)/kg of Ad-CAGoptZGP induced strong Ebola glycoprotein (GP) specific CD8+ and CD4+ T cell responses and Ebola GP-specific antibodies in systemic and mucosal compartments and was partially (67%) protective from challenge 62 days after immunization. The same dose given by the SL route induced Ebola GP-specific CD8+ T cell responses similar to that of intramuscular (IM) injection, however, the Ebola GP-specific antibody response was low. All primates succumbed to infection. Three primates were then given the vaccine in a formulation that improved the immune response to Ebola in rodents. Three primates were immunized with 2.0×10(10) ivp/kg of vaccine by the SL route. Diverse populations of polyfunctional Ebola GP-specific CD4+ and CD8+ T cells and significant anti-Ebola GP antibodies were present in samples collected 150 days after respiratory immunization. The formulated vaccine was fully protective against challenge 21 weeks after immunization. While diverse populations of Ebola GP-specific CD4+ T cells were produced after SL immunization, antibodies were not neutralizing and the vaccine was unprotective. To our knowledge, this is the first time that durable protection from a single dose respiratory adenovirus-based Ebola vaccine has been demonstrated in primates. PMID:25363619

  13. PF-05231023, a long-acting FGF21 analogue, decreases body weight by reduction of food intake in non-human primates.

    PubMed

    Thompson, W Clayton; Zhou, Yingjiang; Talukdar, Saswata; Musante, Cynthia J

    2016-08-01

    PF-05231023, a long-acting FGF21 analogue, is a promising potential pharmacotherapy for the treatment of obesity and associated comorbidities. Previous studies have shown the potential of FGF21 and FGF21-like compounds to decrease body weight in mice, non-human primates, and humans; the precise mechanisms of action remain unclear. In particular, there have been conflicting reports on the degree to which FGF21-induced weight loss in non-human primates is attributable to a decrease in food intake versus an increase in energy expenditure. Here, we present a semi-mechanistic mathematical model of energy balance and body composition developed from similar work in mice. This model links PF-05231023 administration and washout to changes in food intake, which in turn drives changes in body weight. The model is calibrated to and compared with recently published data from cynomolgus macaques treated with PF-05231023, demonstrating its accuracy in describing pharmacotherapy-induced weight loss in these animals. The results are consistent with the hypothesis that PF-05231023 decreases body weight in cynomolgus macaques solely by a reduction in food intake, with no direct effect on energy expenditure. PMID:27405817

  14. The 3R principle and the use of non-human primates in the study of neurodegenerative diseases: the case of Parkinson's disease.

    PubMed

    Vitale, Augusto; Manciocco, Arianna; Alleva, Enrico

    2009-01-01

    The aim of this paper is to offer an ethical perspective on the use of non-human primates in neurobiological studies, using the Parkinson's disease (PD) as an important case study. We refer, as theoretical framework, to the 3R principle, originally proposed by Russell and Burch [Russell, W.M.S., Burch, R.L., 1959. The Principles of Humane Experimental Technique. Universities Federation for Animal Welfare Wheathampstead, England (reprinted in 1992)]. Then, the use of non-human primates in the study of PD will be discussed in relation to the concepts of Replacement, Reduction, and Refinement. Replacement and Reduction result to be the more problematic concept to be applied, whereas Refinement offers relatively more opportunities of improvement. However, although in some cases the 3R principle shows its applicative limits, its value, as conceptual and inspirational tool remains extremely valuable. It suggests to the researchers a series of questions, both theoretical and methodological, which can have the results of improving the quality of life on the experimental models, the quality of the scientific data, and the public perception from the non-scientist community. PMID:18773919

  15. 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

  16. 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

  17. 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

  18. 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

  19. Using PET H2O15 brain imaging to study the functional-anatomical correlates of non-human primate communication.

    PubMed

    Gil-da-Costa, Ricardo; Braun, Allen; Martin, Alex

    2006-03-01

    In this article, we describe methods for using oxygen-15 water (H2O15) positron emission tomography (PET) to explore the functional neuroanatomy of cognition in awake, non-human primates. The discussion is based on a recent study designed to identify regions in the monkey brain associated with perceiving auditory stimuli, and species-specific calls, in particular [Gil-da-Costa et al., Proc. Natl. Acad. Sci. USA 101 (2004) 17516-17521]. Details are provided concerning critical aspects of the experimental paradigm, including pre-scanning habituation sessions to acclimate the animals to the PET scanner environment, and details of a pilot study to determine the auditory stimulus parameters necessary to produce robust activity in brain regions known to process auditory information (belt and parabelt regions of monkey auditory cortex). Methods for acquiring and analyzing PET data to identify significant regions of brain activity in single animals are also presented. PMID:16466931

  20. 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. PMID:23700410

  1. Knowledge-Guided Robust MRI Brain Extraction for Diverse Large-Scale Neuroimaging Studies on Humans and Non-Human Primates

    PubMed Central

    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. PMID:24489639

  2. Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates.

    PubMed

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

    2011-01-01

    Optimal results in the direct brain delivery of brain therapeutics such as growth factors or viral vector into primate brain depend 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 (V(i)) was compared to total volume of distribution (V(d)) versus V(d) within the target putamen. Excellent distribution of contrast agent within the putamen was obtained in eight 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

  3. 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. PMID:25880220

  4. Antipsychotic-Like Effect of the Muscarinic Acetylcholine Receptor Agonist BuTAC in Non-Human Primates

    PubMed Central

    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. PMID:25880220

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

    PubMed Central

    2012-01-01

    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. PMID:22958282

  6. Antagonism of the adenosine A2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model.

    PubMed

    Bleickardt, Carina J; Kazdoba, Tatiana M; Jones, Nicholas T; Hunter, John C; Hodgson, Robert A

    2014-03-01

    Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisia-like behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A2A receptor antagonists for the treatment of antipsychotic-induced movement disorders. PMID:24211858

  7. Transmission dynamics of Cryptosporidium infection in a natural population of non-human primates at Polonnaruwa, Sri Lanka.

    PubMed

    Ekanayake, Dilrukshi K; Welch, David Mark; Kieft, Rudo; Hajduk, Stephen; Dittus, Wolfgang P J

    2007-11-01

    Infections from Cryptosporidium parvum are of interest not only to public health, but also to wildlife conservation, particularly when humans and livestock encroach on nature and thereby increase the risk of cross-species transmissions. To clarify this risk, we used polymerase chain reaction to examine the hypervariable region of the C. parvum 18S rRNA gene in feces from three monkey species. Samples were isolated from regions where disease transmission between monkeys, livestock, and humans was likely (soiled habitat) or unlikely (clean habitat). Monkey individuals, their social groups, and different species shared multiple genotypes/isolates of C. parvum. Ecological and molecular analyses suggested that Cryptosporidium infection among Toque macaques in soiled habitats was mainly the bovine genotype C. parvum. Monkeys inhabiting clean habitat, particularly gray and purple-faced langurs, lacked Cryptosporidium species/types associated with bovines. Livestock apparently was a main source of infection for wild primates. PMID:17984333

  8. 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

  9. Chronic cocaine self-administration is associated with altered functional activity in the temporal lobes of non human primates.

    PubMed

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

    2006-06-01

    Previous studies utilizing a nonhuman primate model have shown that cocaine self-administration in its initial stages is accompanied by alterations in functional activity largely within the prefrontal cortex and ventral striatum. Continued cocaine exposure may considerably change this response. The purpose of the present investigation was to characterize the effects of reinforcing doses of cocaine on cerebral metabolism in a nonhuman primate model of cocaine self-administration, following an extended history of cocaine exposure, using the quantitative 2-[(14)C]deoxyglucose (2-DG) method. Rhesus monkeys were trained to self-administer 0.03 mg/kg/injection (n = 4) or 0.3 mg/kg/injection (n = 4) cocaine and compared to monkeys trained to respond under an identical schedule of food reinforcement (n = 6). Monkeys received 30 reinforcers per session for a total of 100 sessions. Metabolic mapping was conducted at the end of the final session. After this extended history, cocaine self-administration dose-dependently reduced glucose utilization throughout the striatum and prefrontal cortex similarly to the initial stages of self-administration. However, glucose utilization was also decreased in a dose-independent manner in large portions of the temporal lobe including the amygdala, hippocampus and surrounding neocortex. The recruitment of temporal structures indicates that the pattern of changes in functional activity has undergone significant expansion beyond limbic regions into association areas that mediate higher order cognitive and emotional processing. These data strongly contribute to converging evidence from human studies demonstrating structural and functional abnormalities in temporal and prefrontal areas of cocaine abusers, and suggest that substance abusers may undergo progressive cognitive decline with continued exposure to cocaine. PMID:16820001

  10. Chronic Continuous Exenatide Infusion Does Not Cause Pancreatic Inflammation and Ductal Hyperplasia in Non-Human Primates

    PubMed Central

    Fiorentino, Teresa Vanessa; Owston, Michael; Abrahamian, Gregory; La Rosa, Stefano; Marando, Alessandro; Perego, Carla; Di Cairano, Eliana S.; Finzi, Giovanna; Capella, Carlo; Sessa, Fausto; Casiraghi, Francesca; Paez, Ana; Adivi, Ashwin; Davalli, Alberto; Fiorina, Paolo; Guardado Mendoza, Rodolfo; Comuzzie, Anthony G.; Sharp, Mark; DeFronzo, Ralph A.; Halff, Glenn; Dick, Edward J.; Folli, Franco

    2016-01-01

    In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67–positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67–positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67–positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30–positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates. PMID:25447052

  11. 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

  12. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates.

    PubMed

    Nikolich-Zugich, Janko; Messaoudi, Ilhem

    2005-11-01

    Humanity has been obsessed with extending life span and reversing the aging process throughout recorded history and this quest most likely preceded the invention of the written word. The search for eternal youth has spurred holy wars and precipitated the discovery of the new world (the 'Fountain of youth'). It therefore comes as no surprise that an increasingly greater amount of research effort is dedicated to improve our understanding of the aging process and finding interventions to moderate its impact on health. Caloric restriction (CR) is the only intervention in biology that consistently extends maximal and median life span in a variety of short-lived species. Several theories to explain the mechanisms of action of CR have been put forth, including the possibility that CR acts by retarding immune senescence. The question remains, however, whether CR will have the same beneficial impact on human aging, and, if so, how long does CR need to last to produce beneficial effects. To address this question, several groups initiated long-term studies in Rhesus macaques (RM) in the 1980s. Here, we review published data describing the impact of CR on the aging immune system of mice and primates, and discuss our unpublished data that delineate similarities and differences in the effects of CR upon T cell aging and homeostasis between these two models. PMID:16087306

  13. Differential effects of Denileukin Diftitox IL-2 immunotoxin on NK and regulatory T cells in non-human primates

    PubMed Central

    Yamada, Yohei; Aoyama, Akihiro; Tocco, Georges; Boskovic, Svjetlan; Nadazdin, Ognjenka; Alessandrini, Alessandro; Madsen, Joren C.; Cosimi, A. Benedict; Benichou, Gilles; Kawai, Tatsuo

    2012-01-01

    Denileukin Diftitox (DD), a fusion protein comprised of IL-2 and diphtheria toxin was initially expected to enhance anti-tumor immunity by selectively eliminating regulatory T cells (Tregs) displaying the high affinity IL-2R (α-β-γ trimers). While DD has been shown to deplete some Tregs in primates, its effects on NK cells (CD16+CD8+NKG2A+CD3−), which constitutively express the intermediate affinity IL-2R (β-γ dimers) and play a critical role in anti-tumor immunity, are still unknown. To address this question, cynomolgus monkeys were injected intravenously with two different doses of DD (8 or 18 μg/Kg). This treatment resulted in a rapid but short-term reduction in detectable peripheral blood resting Tregs (R-Tregs: CD4+CD45RA+Foxp3+) and a transient increase in the number of activated Tregs (A-Tregs: CD4+CD45RA−Foxp3high) followed by their partial depletion (50–60%). On the other hand, all NK cells were deleted immediately and durably after DD administration. This difference was not due to a higher binding or internalization of DD by NK cells as compared to Tregs. Co-administration of DD with IL-15, which binds to IL-2Rβ-γ, abrogated DD-induced NK cell deletion in vitro and in vivo while it did not affect Tregs elimination. Taken together, these results show that DD exerts a potent cytotoxic effect on NK cells, a phenomenon which might impair its anti-tumoral properties. However, co-administration of IL-15 with DD could alleviate this problem by selectively protecting potentially oncolytic NK cells while allowing the depletion of immunosuppressive regulatory T cells in cancer patients. PMID:22586034

  14. The induction of bone formation by smart biphasic hydroxyapatite tricalcium phosphate biomimetic matrices in the non-human primate Papio ursinus

    PubMed Central

    Ripamonti, U; Richter, P W; Nilen, R W N; Renton, L

    2008-01-01

    Long-term studies in the non-human primate Chacma baboon Papio ursinus were set to investigate the induction of bone formation by biphasic hydroxyapatite/p-tricalcium phosphate (HA/β-TCP) biomimetic matrices. HA/β-TCP biomimetic matrices in a pre-sinter ratio (wt%) of 40/60 and 20/80, respectively, were sintered and implanted in the rectus abdominis and in calvarial defects of four adult baboons. The post-sinter phase content ratios were 19/81 and 4/96, respectively. Morphological analyses on day 90 and 365 showed significant induction of bone formation within concavities of the biomimetic matrices with substantial bone formation by induction and resorption/dissolution of the implanted matrices. One year after implantation in calvarial defects, 4/96 biphasic biomimetic constructs showed prominent induction of bone formation with significant dissolution of the implanted scaffolds. The implanted smart biomimetic matrices induce de novo bone formation even in the absence of exogenously applied osteogenic proteins of the transforming growth factor-β(TGF-β) superfamily. The induction of bone formation biomimetizes the remodelling cycle of the cortico-cancellous bone of primates whereby resorption lacunae, pits and concavities cut by osteoclastogenesis are regulators of bone formation by induction. The concavities assembled in HA/β-TCP biomimetic bioceramics are endowed with multifunctional pleiotropic self-assembly capacities initiating and promoting angiogenesis and bone formation by induction. Resident mesenchymal cells differentiate into osteoblastic cell lines expressing, secreting and embedding osteogenic soluble molecular signals of the TGF-β superfamily within the concavities of the biomimetic matrices initiating bone formation as a secondary response. PMID:18363843

  15. Giardia duodenalis assemblages and Entamoeba species infecting non-human primates in an Italian zoological garden: zoonotic potential and management traits

    PubMed Central

    2011-01-01

    Background Giardia duodenalis and Entamoeba spp. are among the most common intestinal human protozoan parasites worldwide and they are frequently reported in captive non-human primates (NHP). From a public health point of view, infected animals in zoos constitute a risk for animal caretakers and visitors. In this study we carried out the molecular identification of G. duodenalis and Entamoeba spp. from nine species of primates housed in the zoological garden of Rome, to better ascertain their occurrence and zoonotic potential. Results G. duodenalis was found only in Lemur catta (47.0%). Entamoeba spp. were detected in all species studied, with the exception of Eulemur macaco and Varecia rubra. The number of positive pools ranged from 5.9% in L. catta to 81.2% in Mandrillus sphinx; in Pan troglodytes the observed prevalence was 53.6%. A mixed Entamoeba-Giardia infection was recorded only in one sample of L. catta. All G. duodenalis isolates belonged to the zoonotic assemblage B, sub assemblage BIV. Three Entamoeba species were identified: E. hartmanni, E. coli and E. dispar. Conclusions Our results highlight the importance of regularly testing animals kept in zoos for the diagnosis of zoonotic parasites, in order to evaluate their pathogenic role in the housed animals and the zoonotic risk linked to their presence. A quick detection of the arrival of pathogens into the enclosures could also be a prerequisite to limit their spread into the structure via the introduction of specific control strategies. The need for molecular identification of some parasite species/genotype in order to better define the zoonotic risk is also highlighted. PMID:21988762

  16. Immunoreactivity for Choline Acetyltransferase of Peripheral-Type (pChAT) in the Trigeminal Ganglion Neurons of the Non-Human Primate Macaca fascicularis

    PubMed Central

    Koga, Tsuneyuki; Bellier, Jean-Pierre; Kimura, Hiroshi; Tooyama, Ikuo

    2013-01-01

    Transcripts of the choline acetyltransferase (ChAT) gene reveal a number of different splice variants including ChAT of a peripheral type (pChAT). Immunohistochemical staining of the brain using an antibody against pChAT clearly revealed peripheral cholinergic neurons, but failed to detect cholinergic neurons in the central nervous system. In rodents, pChAT-immunoreactivity has been detected in cholinergic parasympathetic postganglionic and enteric ganglion neurons. In addition, pChAT has been observed in non-cholinergic neurons such as peripheral sensory neurons in the trigeminal and dorsal root ganglia. The common type of ChAT (cChAT) has been investigated in many parts of the brain and the spinal cord of non-human primates, but little information is available about the localization of pChAT in primate species. Here, we report the detection of pChAT immunoreactivity in trigeminal ganglion (TG) neurons and its co-localization with Substance P (SP) and/or calcitonin gene-related peptide (CGRP) in the cynomolgus monkey, Macaca fascicularis. Neurons positive for pChAT were observed in a rather uniform pattern in approximately half of the trigeminal neurons throughout the TG. Most pChAT-positive neurons had small or medium-sized cell bodies. Double-immunofluorescence staining showed that 85.1% of SP-positive cells and 74.0% of CGRP-positive cells exhibited pChAT immunoreactivity. Most pChAT-positive cells were part of a larger population of neurons that co-expressed SP and/or CGRP. PMID:23720604

  17. Reliability of signals from a chronically implanted, silicon-based electrode array in non-human primate primary motor cortex.

    PubMed

    Suner, Selim; Fellows, Matthew R; Vargas-Irwin, Carlos; Nakata, Gordon Kenji; Donoghue, John P

    2005-12-01

    related signals for neural prostheses, as well as for fundamental research applications, can be reliably obtained for long time periods using a monolithic microelectrode array in primate MI and potentially from other cortical areas as well. PMID:16425835

  18. The induction of endochondral bone formation by transforming growth factor-β3: experimental studies in the non-human primate Papio ursinus

    PubMed Central

    Ripamonti, Ugo; Nathaniel Ramoshebi, L; Teare, June; Renton, Louise; Ferretti, Carlo

    2008-01-01

    Abstract Transforming growth factor-β3 (TGF-β3), a multi-functional growth modulator of embryonic development, tissue repair and morphogenesis, immunoregulation, fibrosis, angiogenesis and carcinogenesis, is the third mammalian isoform of the TGF-β subfamily of proteins. The pleiotropism of the signalling proteins of the TGF-β superfamily, including the TGF-β proteins per se, are highlighted by the apparent redundancy of soluble molecular signals initiating de novo endochondral bone induction in the primate only. In the heterotopic bioassay for bone induction in the subcutaneous site of rodents, the TGF-β3 isoform does not initiate endochondral bone formation. Strikingly and in marked contrast to the rodent bioassay, recombinant human (h)TGF-β3, when implanted in the rectus abdominis muscle of adult non-human primates Papio ursinus at doses of 5, 25 and 125 μg per 100 mg of insoluble collagenous matrix as carrier, induces rapid endochondral bone formation resulting in large corticalized ossicles by day 30 and 90. In the same animals, the delivery of identical or higher doses of theTGF-β3 protein results in minimal repair of calvarial defects on day 30 with limited bone regeneration across the pericranial aspect of the defects on day 90. Partial restoration of the bone induction cascade by the hTGF-β3 protein is obtained by mixing the hTGF-β3 device with minced fragments of autogenous rectus abdominis muscle thus adding responding stem cells for further bone induction by the hTGF-β3 protein. The observed limited bone induction in hTGF-β3/treated and untreated calvarial defects in Papio ursinus and therefore by extension to Homo sapiens, is due to the influence of Smad-6 and Smad-7 down-stream antagonists of the TGF-β signalling pathway. RT-PCR, Western and Northern blot analyses of tissue specimens generated by the TGF-β3 isoform demonstrate robust expression of Smad-6 and Smad-7 in orthotopic calvarial sites with limited expression in heterotopic

  19. Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates

    SciTech Connect

    Sekizawa, Shin-ichi; Joad, Jesse P.; Pinkerton, Kent E.; Bonham, Ann C.

    2010-01-15

    Exposing children to secondhand tobacco smoke (SHS) is associated with increased risk for asthma, bronchiolitis and SIDS. The role for changes in the developing CNS contributing to these problems has not been fully explored. We used rhesus macaques to test the hypothesis that SHS exposure during development triggers neuroplastic changes in the nucleus tractus solitarius (NTS), where lung sensory information related to changes in airway and lung function is first integrated. Pregnant monkeys were exposed to filtered air (FA) or SHS for 6 h/day, 5 days/week starting at 50-day gestational age. Mother/infant pairs continued the exposures postnatally to age 3 or 13 months, which may be equivalent to approximately 1 or 4 years of human age, respectively. Whole-cell recordings were made of second-order NTS neurons in transverse brainstem slices. To target the consequences of SHS exposure based on neuronal subgroups, we classified NTS neurons into two phenotypes, rapid-onset spiking (RS) and delayed-onset spiking (DS), and then evaluated intrinsic and synaptic excitabilities in FA-exposed animals. RS neurons showed greater cell excitability especially at age of 3 months while DS neurons received greater amplitudes of excitatory postsynaptic currents (EPSCs). Developmental neuroplasticity such as increases in intrinsic and synaptic excitabilities were detected especially in DS neurons. In 3 month olds, SHS exposure effects were limited to excitatory changes in RS neurons, specifically increases in evoked EPSC amplitudes and increased spiking responses accompanied by shortened action potential width. By 13 months, the continued SHS exposure inhibited DS neuronal activity; decreases in evoked EPSC amplitudes and blunted spiking responses accompanied by prolonged action potential width. The influence of SHS exposure on age-related and phenotype specific changes may be associated with age-specific respiratory problems, for which SHS exposure can increase the risk, such as SIDS

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

    PubMed Central

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

    2014-01-01

    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 (2.5 mg/kg bw) or NaOCN (50 mg/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 ~ 80X faster in the nervous system (14 milliseconds 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 macaca fascicularis, plasma CDC changed proportionally to total proteins (r=0.43; p<0.001). The plasma CDC was ~ 2X 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. PMID:24500607

  1. Assessment of placental transfer and the effect on embryo-fetal development of a humanized monoclonal antibody targeting lymphotoxin-alpha in non-human primates.

    PubMed

    Wang, Hong; Schuetz, Chris; Arima, Akihiro; Chihaya, Yutaka; Weinbauer, Gerhard F; Habermann, Gunnar; Xiao, Jim; Woods, Cynthia; Grogan, Jane; Gelzleichter, Thomas; Cain, Gary

    2016-08-01

    An enhanced embryo-fetal development study was conducted in cynomolgus monkeys using pateclizumab, a humanized IgG1 monoclonal antibody (mAb) targeting lymphotoxin-alpha. Pateclizumab administration between gestation days (GD) 20 and 132 did not induce maternal or developmental toxicities. The ratio of fetal-to-maternal serum concentration of pateclizumab was 0.73% on GD 50 and 61% by GD 139. Decreased fetal inguinal lymph node-to-body weight ratio was present in the high-dose group without microscopic abnormalities, a change attributable to inhibition of lymphocyte recruitment, which is a pharmacologic effect of pateclizumab during late lymph node development. The effect was observed in inguinal but not submandibular or mesenteric lymph nodes; this was attributed to differential susceptibility related to sequential lymph node development. Placental transfer of therapeutic IgG1 antibodies; thus, begins during the first trimester in non-human primates. Depending on the potency and dose levels administered, antibody levels in the fetus may be pharmacologically or toxicologically relevant. PMID:27211603

  2. Testing the H56 Vaccine Delivered in 4 Different Adjuvants as a BCG-Booster in a Non-Human Primate Model of Tuberculosis

    PubMed Central

    Billeskov, Rolf; Tan, Esterlina V.; Cang, Marjorie; Abalos, Rodolfo M.; Burgos, Jasmin; Pedersen, Bo Vestergaard; Christensen, Dennis; Agger, Else Marie; Andersen, Peter

    2016-01-01

    The search for new and improved tuberculosis (TB) vaccines has focused on IFN-γ both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-γ in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31® adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-γ-responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-γ production did not correlate with or predict disease outcome. This study’s main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB. PMID:27525651

  3. 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

  4. Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Non-Human Primates1

    PubMed Central

    Thompson, Elizabeth A; Liang, Frank; Lindgren, Gustaf; Sandgren, Kerrie J; Quinn, Kylie M; Darrah, Patricia A; Koup, Richard A; Seder, Robert A; Kedl, Ross M; Loré, Karin

    2015-01-01

    Non-live vaccine platforms that induce potent cellular immune responses in mucosal tissue would have broad application for vaccines against infectious diseases and tumors. Induction of cellular immunity could be optimized by targeted activation of multiple innate and co-stimulatory signaling pathways, such as CD40 or toll-like receptors (TLRs). In this study, we evaluated immune activation and elicitation of T cell responses in non-human primates (NHPs) after immunization with peptide antigens adjuvanted with an agonistic αCD40Ab, with or without the TLR3 ligand poly IC:LC. We found that intravenous administration of the αCD40Ab induced rapid and transient innate activation characterized by IL-12 production and upregulated co-stimulatory and lymph node homing molecules on dendritic cells. Using fluorescently-labeled Abs for in vivo tracking, the αCD40Ab bound to all leucocytes, except T cells, and disseminated to multiple organs. CD4+ and CD8+ T cell responses were significantly enhanced when the αCD40Ab was co-administered with poly IC:LC compared to either adjuvant given alone and were almost exclusively compartmentalized to the lung. Notably, antigen-specific T cells in the bronchoalveolar lavage were sustained at ~5–10%. These data indicate that systemic administration of αCD40Ab may be particularly advantageous for vaccines and/or therapies requiring T cell immunity in the lung. PMID:26123354

  5. 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. PMID:26732424

  6. 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.

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

    PubMed

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

    2015-03-01

    Autologous transplantation of patient-specific induced pluripotent stem cell (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. Postmortem 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

  8. Testing the H56 Vaccine Delivered in 4 Different Adjuvants as a BCG-Booster in a Non-Human Primate Model of Tuberculosis.

    PubMed

    Billeskov, Rolf; Tan, Esterlina V; Cang, Marjorie; Abalos, Rodolfo M; Burgos, Jasmin; Pedersen, Bo Vestergaard; Christensen, Dennis; Agger, Else Marie; Andersen, Peter

    2016-01-01

    The search for new and improved tuberculosis (TB) vaccines has focused on IFN-γ both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-γ in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31® adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-γ-responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-γ production did not correlate with or predict disease outcome. This study's main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB. PMID:27525651

  9. 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

  10. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates.

    PubMed

    Gray, S J; Nagabhushan Kalburgi, S; McCown, T J; Jude Samulski, R

    2013-04-01

    Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ∼2 × 10(12) vector genome (vg) per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases. PMID:23303281

  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. 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.

  12. 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.

  13. Generation and characterization of large-particle aerosols using a center flow tangential aerosol generator with a non-human-primate, head-only aerosol chamber.

    PubMed

    Bohannon, J Kyle; Lackemeyer, Matthew G; Kuhn, Jens H; Wada, Jiro; Bollinger, Laura; Jahrling, Peter B; Johnson, Reed F

    2015-01-01

    Aerosol droplets or particles produced from infected respiratory secretions have the potential to infect another host through inhalation. These respiratory particles can be polydisperse and range from 0.05 to 500 µm in diameter. Animal models of infection are generally established to facilitate the potential licensure of candidate prophylactics and/or therapeutics. Consequently, aerosol-based animal infection models are needed to properly study and counter airborne infections. Ideally, experimental aerosol exposure should reliably result in animal disease that faithfully reproduces the modeled human disease. Few studies have been performed to explore the relationship between exposure particle size and induced disease course for infectious aerosol particles. The center flow tangential aerosol generator (CenTAG™) produces large-particle aerosols capable of safely delivering a variety of infectious aerosols to non-human primates (NHPs) within a Class III Biological Safety Cabinet (BSC) for establishment or refinement of NHP infectious disease models. Here, we report the adaptation of this technology to the Animal Biosafety Level 4 (ABSL-4) environment for the future study of high-consequence viral pathogens and the characterization of CenTAG™-created sham (no animal, no virus) aerosols using a variety of viral growth media and media supplements. PMID:25970823

  14. Immunogenicity and some safety features of a VEGF-based cancer therapeutic vaccine in rats, rabbits and non-human primates.

    PubMed

    Morera, Yanelys; Bequet-Romero, Mónica; Ayala, Marta; Velazco, Jorge Castro; Pérez, Pedro Puente; Alba, Jesús Suárez; Ancizar, Julio; Rodríguez, Meilyn; Cosme, Karelia; Gavilondo, Jorge V

    2010-04-26

    We have developed a cancer vaccine candidate (hereafter denominated CIGB-247), based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, and the adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). In mice, previous work of our group had shown that vaccination with CIGB-247 extended tumor-take time, slowed tumor growth, and increased animal survival. Immunization elicited anti-human and murine VEGF-neutralizing antibodies, and spleen cells of vaccinated mice are cytotoxic in vitro to tumor cells that produce VEGF. We have now tested the immunogenicity of CIGB-247 in Wistar rats, New Zealand White rabbits and the non-human primate Chlorocebus aethiops sabaeus. Using weekly, biweekly and biweekly plus montanide immunization schemes, all three species develop antigen-specific IgG antibodies that can block the interaction of VEGF and VEGF receptor 2 in an ELISA assay. Antibody titers decline after vaccination stops, but can be boosted with new immunizations. In monkeys, DTH and direct cell cytotoxicity experiments suggest that specific T-cell responses are elicited by vaccination. Immunization with CIGB-247 had no effect on normal behavior, hematology, blood biochemistry and histology of critical organs, in the tested animals. Skin deep wound healing was not affected in vaccinated rats and monkeys. PMID:20197134

  15. Pharmacokinetics, Metabolism, Biodistribution, Radiation Dosimetry, and Toxicology of 18F-Fluoroacetate (18F-FACE) in Non-human Primates

    PubMed Central

    Nishii, Ryuichi; Tong, William; Wendt, Richard; Soghomonyan, Suren; Mukhopadhyay, Uday; Balatoni, Julius; Mawlawi, Osama; Bidaut, Luc; Tinkey, Peggy; Borne, Agatha; Alauddin, Mian; Gonzalez-Lepera, Carlos; Yang, Bijun; Gelovani, Juri G.

    2014-01-01

    Introduction To facilitate the clinical translation of 18F-fluoroacetate (18F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of 18F-FACE were determined in non-human primates. Methods 18F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with 18F-FACE (165.4± 28.5 MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0–30 min post-injection and static whole-body PET imaging at 40, 100, and 170 min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of 18F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of 18F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of 18F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans. Results The blood clearance of 18F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of 18F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that 18F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180 min after the 18F-FACE injection. The uptake of free 18F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90–7.81 mSv from the administration of 185

  16. Reversible Femtosecond Laser-Assisted Myopia Correction: A Non-Human Primate Study of Lenticule Re-Implantation after Refractive Lenticule Extraction

    PubMed Central

    Chaurasia, Shyam S.; Lee, Wing S.; Tan, Donald T.; Mehta, Jodhbir S.

    2013-01-01

    LASIK (laser-assisted in situ keratomileusis) is a common laser refractive procedure for myopia and astigmatism, involving permanent removal of anterior corneal stromal tissue by excimer ablation beneath a hinged flap. Correction of refractive error is achieved by the resulting change in the curvature of the cornea and is limited by central corneal thickness, as a thin residual stromal bed may result in biomechanical instability of the cornea. A recently developed alternative to LASIK called Refractive Lenticule Extraction (ReLEx) utilizes solely a femtosecond laser (FSL) to incise an intrastromal refractive lenticule (RL), which results in reshaping the corneal curvature and correcting the myopia and/or astigmatism. As the RL is extracted intact in the ReLEx, we hypothesized that it could be cryopreserved and re-implanted at a later date to restore corneal stromal volume, in the event of keratectasia, making ReLEx a potentially reversible procedure, unlike LASIK. In this study, we re-implanted cryopreserved RLs in a non-human primate model of ReLEx. Mild intrastromal haze, noted during the first 2 weeks after re-implantation, subsided after 8 weeks. Refractive parameters including corneal thickness, anterior curvature and refractive error indices were restored to near pre-operative values after the re-implantation. Immunohistochemistry revealed no myofibroblast formation or abnormal collagen type I expression after 8 weeks, and a significant attenuation of fibronectin and tenascin expression from week 8 to 16 after re-implantation. In addition, keratocyte re-population could be found along the implanted RL interfaces. Our findings suggest that RL cryopreservation and re-implantation after ReLEx appears feasible, suggesting the possibility of potential reversibility of the procedure, and possible future uses of RLs in treating other corneal disorders and refractive errors. PMID:23826194

  17. Motion compensation for brain PET imaging using wireless MR active markers in simultaneous PET-MR: phantom and non-human primate studies

    PubMed Central

    Huang, Chuan; Ackerman, Jerome L.; Petibon, Yoann; Normandin, Marc D.; Brady, Thomas J.; El Fakhri, Georges; Ouyang, Jinsong

    2014-01-01

    Brain PET scanning plays an important role in the diagnosis, prognostication and monitoring of many brain diseases. Motion artifacts from head motion are one of the major hurdles in brain PET. In this work, we propose to use wireless MR active markers to track head motion in real time during a simultaneous PET-MR brain scan and incorporate the motion measured by the markers in the listmode PET reconstruction. Several wireless MR active markers and a dedicated fast MR tracking pulse sequence module were built. Data were acquired on an ACR Flangeless PET phantom with multiple spheres and a non-human primate with and without motion. Motions of the phantom and monkey’s head were measured with the wireless markers using a dedicated MR tracking sequence module. The motion PET data were reconstructed using list-mode reconstruction with and without motion correction. Static reference was used as gold standard for quantitative analysis. The motion artifacts, which were prominent on the images without motion correction, were eliminated by the wireless marker based motion correction in both the phantom and monkey experiments. Quantitative analysis was performed on the phantom motion data from 24 independent noise realizations. The reduction of bias of sphere-to-background PET contrast by active marker based motion correction ranges from 26% to 64% and 17% to 25% for hot (i.e., radioactive) and cold (i.e., non-radioactive) spheres, respectively. The motion correction improved the channelized Hotelling observer signal-to-noise ratio of the spheres by 1.2 to 6.9 depending on their locations and sizes. The proposed wireless MR active marker based motion correction technique removes the motion artifacts in the reconstructed PET images and yields accurate quantitative values. PMID:24418501

  18. Motion compensation for brain PET imaging using wireless MR active markers in simultaneous PET-MR: phantom and non-human primate studies.

    PubMed

    Huang, Chuan; Ackerman, Jerome L; Petibon, Yoann; Normandin, Marc D; Brady, Thomas J; El Fakhri, Georges; Ouyang, Jinsong

    2014-05-01

    Brain PET scanning plays an important role in the diagnosis, prognostication and monitoring of many brain diseases. Motion artifacts from head motion are one of the major hurdles in brain PET. In this work, we propose to use wireless MR active markers to track head motion in real time during a simultaneous PET-MR brain scan and incorporate the motion measured by the markers in the listmode PET reconstruction. Several wireless MR active markers and a dedicated fast MR tracking pulse sequence module were built. Data were acquired on an ACR Flangeless PET phantom with multiple spheres and a non-human primate with and without motion. Motions of the phantom and monkey's head were measured with the wireless markers using a dedicated MR tracking sequence module. The motion PET data were reconstructed using list-mode reconstruction with and without motion correction. Static reference was used as gold standard for quantitative analysis. The motion artifacts, which were prominent on the images without motion correction, were eliminated by the wireless marker based motion correction in both the phantom and monkey experiments. Quantitative analysis was performed on the phantom motion data from 24 independent noise realizations. The reduction of bias of sphere-to-background PET contrast by active marker based motion correction ranges from 26% to 64% and 17% to 25% for hot (i.e., radioactive) and cold (i.e., non-radioactive) spheres, respectively. The motion correction improved the channelized Hotelling observer signal-to-noise ratio of the spheres by 1.2 to 6.9 depending on their locations and sizes. The proposed wireless MR active marker based motion correction technique removes the motion artifacts in the reconstructed PET images and yields accurate quantitative values. PMID:24418501

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

    PubMed Central

    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. PMID:26252520

  20. Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy.

    PubMed

    Meneghini, Vasco; Lattanzi, Annalisa; Tiradani, Luigi; Bravo, Gabriele; Morena, Francesco; Sanvito, Francesca; Calabria, Andrea; Bringas, John; Fisher-Perkins, Jeanne M; Dufour, Jason P; Baker, Kate C; Doglioni, Claudio; Montini, Eugenio; Bunnell, Bruce A; Bankiewicz, Krystof; Martino, Sabata; Naldini, Luigi; Gritti, Angela

    2016-01-01

    Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD or Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gene therapy (GT) as a rapid and effective intervention to provide pervasive supply of therapeutic lysosomal enzymes in CNS tissues of MLD and GLD mice. Here, we investigated whether this strategy is similarly effective in juvenile non-human primates (NHP). To provide proof of principle for tolerability and biological efficacy of the strategy, we established a comprehensive study in normal NHP delivering a clinically relevant lentiviral vector encoding for the human ARSA transgene. Then, we injected a lentiviral vector coding for the human GALC transgene in Krabbe-affected rhesus macaques, evaluating for the first time the therapeutic potential of lentiviral GT in this unique LSD model. We showed favorable safety profile and consistent pattern of LV transduction and enzyme biodistribution in the two models, supporting the robustness of the proposed GT platform. We documented moderate inflammation at the injection sites, mild immune response to vector particles in few treated animals, no indication of immune response against transgenic products, and no molecular evidence of insertional genotoxicity. Efficient gene transfer in neurons, astrocytes, and oligodendrocytes close to the injection sites resulted in robust production and extensive spreading of transgenic enzymes in the whole CNS and in CSF, leading to supraphysiological ARSA activity in normal NHP and close to physiological GALC activity in the Krabbe NHP, in which biological efficacy was associated with preliminary indication of therapeutic benefit. These results support the rationale for the clinical translation of intracerebral lentiviral GT to address CNS pathology in MLD, GLD, and other neurodegenerative LSD. PMID

  1. 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. PMID:25933796

  2. Testicular recovery after irradiation differs in prepubertal and pubertal non-human primates, and can be enhanced by autologous germ cell transplantation

    PubMed Central

    Jahnukainen, Kirsi; Ehmcke, Jens; Quader, Mubina A.; Saiful Huq, M.; Epperly, Michael W.; Hergenrother, Scott; Nurmio, Mirja; Schlatt, Stefan

    2011-01-01

    BACKGROUND Although infertility is a serious concern in survivors of pediatric cancers, little is known about the influence of the degree of sexual maturation at the time of irradiation on spermatogenic recovery after treatment. Thus, we address this question in a non-human primate model, the rhesus monkey (Macaca mulatta). METHODS Two pubertal (testis size 3 and 6.5 ml, no sperm in ejaculate) and four prepubertal (testis size 1 ml, no sperm in ejaculate) macaques were submitted to a single fraction of testicular irradiation (10 Gy). Unilateral autologous transfer of cryopreserved testis cells was performed 2 months after irradiation. Testicular volume, histology and semen parameters were analyzed to assess irradiation effects and testicular recovery. RESULTS Irradiation provoked acute testis involution only in the two pubertal monkeys. Subsequently, testis sizes recovered and sperm was present in the ejaculates. Longitudinal outgrowth of seminiferous tubules continued, and, in testes without autologous cell transfer, 4–22% of tubular cross sections showed spermatogenesis 2 years after irradiation. In contrast, the four prepubertal monkeys showed neither a detectable involution as direct response to irradiation, nor a detectable growth of seminiferous tubules later. However, two of these animals showed spermarche 2 years after irradiation, and 8–12% of tubules presented spermatogenesis. One prepubertally irradiated monkey presented fast growth of one testis after cell transfer, and showed spermarche 1 year after irradiation. The infused testis had spermatogenesis in 70% of the tubules. The contralateral testis remained smaller. CONCLUSION We conclude that irradiation before puberty has a severe detrimental effect on outgrowth of seminiferous tubules. But, within the seminiferous epithelium, spermatogenetic recovery occurs at a low rate with no detectable relation to the maturity of the epithelium at irradiation. We also show that autologous testis cell

  3. 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

  4. 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

  5. Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment.

    PubMed

    Csiszar, Anna; Sosnowska, Danuta; Wang, Mingyi; Lakatta, Edward G; Sonntag, William E; Ungvari, Zoltan

    2012-08-01

    There is increasing evidence that age-associated chronic low-grade inflammation promotes the development of both large-vessel disease (myocardial infarction, stroke, peripheral arterial disease) and small-vessel pathologies (including vascular cognitive impairment) in older persons. However, the source of age-related chronic vascular inflammation remains unclear. To test the hypothesis that cell-autonomous mechanisms contribute to the proinflammatory changes in vascular phenotype that accompanies advancing age, we analyzed the cytokine secretion profile of primary vascular smooth muscle cells (VSMCs) derived from young (∼13 years old) and aged (∼21 years old) Macaca mulatta. Aged VSMCs cultured in the absence of systemic factors exhibited significantly increased secretion of interleukin-1β, MCP-1, and tumor necrosis factorα compared with young control cells. Secretion of interleukin-6 also tended to increase in aged VSMCs. This age-associated proinflammatory shift in the cellular secretory phenotype was associated with an increased mitochondrial O(2)(-) production and nuclear factor κ-light-chain-enhancer of activated B cells activation. Treatment of aged VSMCs with a physiologically relevant concentration of resveratrol (1 μM) exerted significant anti-inflammatory effects, reversing aging-induced alterations in the cellular cytokine secretion profile and inhibiting nuclear factor κ-light-chain-enhancer of activated B cells. Resveratrol also attenuated mitochondrial O(2)(-) production and upregulated the transcriptional activity of Nrf2 in aged VSMCs. Thus, in non-human primates, cell-autonomous activation of nuclear factor κ-light-chain-enhancer of activated B cells and expression of an inflammatory secretome likely contribute to vascular inflammation in aging. Resveratrol treatment prevents the proinflammatory properties of the aged VSMC secretome, an effect that likely contributes to the demonstrated vasoprotective action of resveratrol in animal

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

    PubMed

    Downs, Matthew E; Buch, Amanda; Sierra, Carlos; Karakatsani, Maria Eleni; Teichert, Tobias; 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 (500 kHz, 200-400 kPa, 4-5 μm 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

  7. Bone Defect Regeneration by a Combination of a β-Tricalcium Phosphate Scaffold and Bone Marrow Stromal Cells in a Non-Human Primate Model

    PubMed Central

    Masaoka, Tomokazu; Yoshii, Toshitaka; Yuasa, Masato; Yamada, Tsuyoshi; Taniyama, Takashi; Torigoe, Ichiro; Shinomiya, Kenichi; Okawa, Atsushi; Morita, Sadao; Sotome, Shinichi

    2016-01-01

    Background: Reconstruction of large bone defects is a great challenge in orthopedic research. In the present study, we prepared composites of bone marrow-derived stromal cells (BMSCs) and β-tricalcium phosphate (β-TCP) with three novel aspects: proliferation of BMSCs with continuous dexamethasone treatment, cell loading under low pressure, and use of autologous plasma as the cell loading medium. The effectiveness of the resulting composite for large bone-defect reconstruction was tested in a non-human primate model, and the bone union capability of the regenerated bones was examined. Materials and Methods: Primary surgery: Bone defects (5 cm long) were created in the left femurs of nine cynomolgus monkeys with resection of the periosteum (five cases) or without resection (four cases), and porous β-TCP blocks were transplanted into the defects. Secondary surgery: Bone marrow aspirates harvested from seven of the nine monkeys were cultured with dexamethasone, and BMSCs were obtained. BMSCs were suspended in autologous plasma and introduced into a porous β-TCP block under low-pressure conditions. The BMSC/β-TCP composites were transplanted into bone defects created at the same sites as the primary surgery. Bone union evaluation: Five regenerated femurs were shortened by osteotomy surgery 8 to 15 months after transplantation of the β-TCP/BMSC composites, and bone union was evaluated radiographically. Results: After the primary surgery and treatment with β-TCP alone, one of the five periosteum-resected monkeys and two of the four periosteum-preserved monkeys exhibited successful bone reconstruction. In contrast, five of the seven cases treated with the β-TCP/MSC composite showed successful bone regeneration. In four of the five osteotomy cases, bone union was confirmed. Conclusion: We validated the effectiveness of a novel β-TCP/BMSC composite for large bone defect regeneration and confirmed the bone union capability of the regenerated bone. PMID:27073583

  8. 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

    2016-09-01

    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. PMID:27523740

  9. Segmental Differences in Radiation-Induced Alterations of Tight Junction-Related Proteins in Non-Human Primate Jejunum, Ileum and Colon.

    PubMed

    Garg, Sarita; Zheng, Junying; Wang, Junru; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin

    2016-01-01

    Dysfunction of the intestinal epithelial barrier and leakage of luminal antigens and bacteria across the barrier have been linked to various human diseases. Intestinal permeability is regulated by intercellular structures, termed "tight junction" (Tj), which are disrupted after total-body irradiation (TBI). In this study, we investigated radiation-induced alterations in Tj-related proteins in the jejunum, ileum and colon of a non-human primate (NHP) model. NHPs were total-body irradiated with 6.7 and 7.4 Gy and intestines were procured at day 4, 7 and 12. Radiation exposure was found to induce significant increases in claudin-10 mRNA early (day 4) in all three gut segments and claudin-4 mRNA levels were repressed through day 12. TNF-alpha was highly induced in the jejunum and colon at early time points, but little induction was found in the ileum. Claudin-1 was induced only in the colon on day 4 postirradiation. Unlike the colon and jejunum, the ileum levels of claudin-7 were significantly downregulated through day 12 postirradiation. Western blot analysis revealed increased levels of claudin-2 on day 4 and of JAM-1 on day 7 postirradiation in all three gut segments. E-cadherin was downregulated on day 4 postirradiation in all segments, but remained reduced in the jejunum only until day 12. Taken together, these data suggest that exposure to radiation causes segment-specific alterations in the expression of Tj-related proteins. Interruption of Tjs may be a key factor contributing to injury to the intestinal mucosal barrier and increased intestinal permeability. PMID:26720804

  10. Effects of the cannabinoid antagonist SR141716 (rimonabant) and d-amphetamine on palatable food and food pellet intake in non-human primates

    PubMed Central

    Foltin, Richard W.; Haney, Margaret

    2007-01-01

    The purpose of this study was to determine if a cannabinoid CB1 receptor antagonist would selectively decrease consumption of highly palatable food in non-human primates. The CB1 receptor antagonist SR141716 (rimonabant; 0.12 - 1.0 mg/kg, i.m.) and the stimulant anorectic drug d-amphetamine (0.12 - 1.0 mg/kg, i.m.) were administered to non-food deprived baboons for the purpose of measuring the effect of each drug on consumption of the normal diet, and a large single meal of a high-carbohydrate candy. Four male and four female baboons had access to food 24 hr each day, but they had to complete a two phase operant procedure in order to eat. Responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on another lever led to food delivery, i.e., a meal. Three days a week baboons received a jelly sugar-coated candy (Skittles®) during the first meal and then pellets were available in subsequent meals. All baboons ate as many individual candies in one meal as they did pellets throughout the entire day. Acute d-amphetamine and, to a lesser extent, SR141716 decreased both candy intake in a single meal and pellet intake in a single meal and over 24 hr. d-Amphetamine, but not SR141716 increased latency to the candy meal and the first pellet meal indicating that the two drugs differentially altered feeding topography. Although males ate more food pellets than females, few other sex differences were observed. Thus, although effective in decreasing food intake, there was no evidence of a specific effect of CB1 receptor antagonism on consumption of a large meal or a palatable food. PMID:17445873