ABSTRACT
Demand for nonhuman primates in research has increased over the past several years, while nonhuman primate supply remains a challenge in the United States. Global nonhuman primate supply issues make it increasingly important to maximize domestic colony production. To explore how housing conditions across primate breeding colonies impact infant survival and animal production more broadly, we collected medical records from 7959 rhesus macaques (Macaca mulatta) and 492 pigtail macaques (Macaca nemestrina) across seven breeding facilities and used generalized mixed-effect modeling to determine prenatal and infant survival odds by housing type and group size. Infant survival odds for each housing type and group size varied for prenatal, neonatal, early infant, and late infant age groups. Odds of prenatal survival were lowest in paired indoor housing and small and medium outdoor groups. No housing type performed better than large outdoor groups for neonatal survival. Odds of early infant survival was greatest in indoor and mixed indoor/outdoor housing compared to large outdoor enclosures. Large outdoor housing was associated with higher survival odds for late infant survival compared to small and medium outdoor housing. These results may influence housing choices at macaque breeding facilities hoping to maximize infant success, although there are relative care costs, the promotion of species-typical behaviors, and infrastructure factors to also consider. Our study used an interinstitutional collaboration that allowed for the analysis of more infant macaque medical records than ever before and used the broad variations across the seven national primate research centers to make the results applicable to many other facilities housing macaques.
Subject(s)
Breeding , Housing, Animal , Humans , Pregnancy , Female , Animals , Macaca mulatta , Macaca nemestrinaABSTRACT
Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.
Subject(s)
Embryonic Stem Cells/cytology , Heart , Myocardial Infarction/pathology , Myocardial Infarction/therapy , Myocytes, Cardiac/cytology , Regeneration , Animals , Arrhythmias, Cardiac/physiopathology , Calcium/metabolism , Cell Survival , Coronary Vessels/physiology , Cryopreservation , Disease Models, Animal , Electrocardiography , Humans , Macaca nemestrina , Male , Mice , Regenerative Medicine/methodsABSTRACT
Juvenile male rhesus monkeys treated with methylphenidate hydrochloride (MPH) to evaluate genetic and behavioral toxicity were observed after 14 mo of treatment to have delayed pubertal progression with impaired testicular descent and reduced testicular volume. Further evaluation of animals dosed orally twice a day with (i) 0.5 mL/kg of vehicle (n = 10), (ii) 0.15 mg/kg of MPH increased to 2.5 mg/kg (low dose, n = 10), or (iii) 1.5 mg/kg of MPH increased to 12.5 mg/kg (high dose, n = 10) for a total of 40 mo revealed that testicular volume was significantly reduced (P < 0.05) at months 15 to 19 and month 27. Testicular descent was significantly delayed (P < 0.05) in the high-dose group. Significantly lower serum testosterone levels were detected in both the low- (P = 0.0017) and high-dose (P = 0.0011) animals through month 33 of treatment. Although serum inhibin B levels were increased overall in low-dose animals (P = 0.0328), differences between groups disappeared by the end of the study. Our findings indicate that MPH administration, beginning before puberty, and which produced clinically relevant blood levels of the drug, impaired pubertal testicular development until â¼5 y of age. It was not possible to resolve whether MPH delayed the initiation of the onset of puberty or reduced the early tempo of the developmental process. Regardless, deficits in testicular volume and hormone secretion disappeared over the 40-mo observation period, suggesting that the impact of MPH on puberty is not permanent.
Subject(s)
Central Nervous System Stimulants/pharmacology , Methylphenidate/pharmacology , Sexual Maturation/drug effects , Animals , Macaca mulatta , Male , Testis/drug effects , Testis/growth & development , Testosterone/bloodABSTRACT
There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Accurate measures of chronological aging are essential for inferences into genetic, demographic, and physiological variables driving differences in NHP lifespan within and between species. Understanding NHP lifespans is relevant to public health because unraveling the demographic, molecular, and clinical bases of health across the life course in translationally relevant NHP species is fundamentally important to the study of human aging. Data from more than 110,000 captive individual NHP were contributed by 15 major research institutions to generate sex-specific Kaplan-Meier survival curves using uniform methods in 12 translational aging models: Callithrix jacchus (common marmoset), Chlorocebus aethiops sabaeus (vervet/African green), Macaca fascicularis (cynomolgus macaque), M. fuscata (Japanese macaque), M. mulatta (rhesus macaque), M. nemestrina (pigtail macaque), M. radiata (bonnet macaque), Pan troglodytes spp. (chimpanzee), Papio hamadryas spp. (baboon), Plecturocebus cupreus (coppery titi monkey), Saguinus oedipus (cotton-top tamarin), and Saimiri spp. (squirrel monkey). After employing strict inclusion criteria, primary analysis results are based on 12,269 NHP that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHP that died of any cause. For the primary analyses, we report ages of 25th, 50th, 75th, and 85th percentiles of survival, maximum observed ages, rates of survivorship, and sex-based differences captured by quantile regression models and Kolmogorov-Smirnov tests. Our findings show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan. Captive NHP used in research are typically euthanized for humane welfare reasons before their natural end of life, often after diagnosis of their first major disease requiring long-term treatment with reduced quality of life (e.g., endometriosis, cancer, osteoarthritis). Supporting the idea that these data are capturing healthspan, for several species typical age at onset of chronic disease is similar to the median lifespan estimates. This data resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. The results clarify the relationships among NHP ages and will provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of the expected survival rates of NHP assigned to studies, providing a metric for comparisons in future studies, and contributing to our understanding of the factors that drive lifespan differences within and among species.
ABSTRACT
Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.
Subject(s)
Models, Genetic , Rare Diseases , Animals , Humans , Rare Diseases/genetics , Genomics , High-Throughput Nucleotide Sequencing , Primates/geneticsABSTRACT
A 3-y-old male pigtailed macaque (Macaca nemestrina) presented for swelling of the left distal forearm and decreased use of the arm. The monkey had been raised at an indoor-outdoor facility in Arizona and transferred to an indoor facility in Washington 2 mo prior to presentation. A preliminary diagnosis of fungal osteomyelitis of the radius was made based on radiographs and Coccidioides titers. In addition to systemic antifungal treatment, surgery was performed to debride the bony lesion and implant polymethylmethacrylate beads impregnanted with the anti-fungal fluconazole. Histologic examination of the debrided material confirmed the diagnosis of fungal osteomyelitis. The surgical procedure resulted in clinical improvement, as evidenced by weight gain and decreased Coccidioides titers. The beads were removed in a second surgery, and the bony lesion completely resolved. With continued systemic fluconazole treatment, the monkey remained healthy with no further evidence of osteomyelitis. Coccidioides is an emerging pathogen that causes significant morbidity and mortality in both humans and animals. Bone infections can be resistant to systemic treatment, and the implantation of fluconazoleimpregnated beads may offer a successful treatment strategy for fungal osteomyelitis.
Subject(s)
Coccidioides , Osteomyelitis , Animals , Antifungal Agents/therapeutic use , Fluconazole/therapeutic use , Humans , Macaca nemestrina , Male , Osteomyelitis/drug therapy , Osteomyelitis/veterinaryABSTRACT
A wide array of pathogens has the potential to injure the fetus and induce teratogenesis, the process by which mutations in fetal somatic cells lead to congenital malformations. Rubella virus was the first infectious disease to be linked to congenital malformations due to an infection in pregnancy, which can include congenital cataracts, microcephaly, hearing impairment and congenital heart disease. Currently, human cytomegalovirus (HCMV) is the leading infectious cause of congenital malformations globally, affecting 1 in every 200 infants. However, our knowledge of teratogenic viruses and pathogens is far from complete. New emerging infectious diseases may induce teratogenesis, similar to Zika virus (ZIKV) that caused a global pandemic in 2016-2017; thousands of neonates were born with congenital microcephaly due to ZIKV exposure in utero, which also included a spectrum of injuries to the brain, eyes and spinal cord. In addition to congenital anomalies, permanent injury to fetal and neonatal organs, preterm birth, stillbirth and spontaneous abortion are known consequences of a broader group of infectious diseases including group B streptococcus (GBS), Listeria monocytogenes, Influenza A virus (IAV), and Human Immunodeficiency Virus (HIV). Animal models are crucial for determining the mechanism of how these various infectious diseases induce teratogenesis or organ injury, as well as testing novel therapeutics for fetal or neonatal protection. Other mammalian models differ in many respects from human pregnancy including placentation, labor physiology, reproductive tract anatomy, timeline of fetal development and reproductive toxicology. In contrast, non-human primates (NHP) most closely resemble human pregnancy and exhibit key similarities that make them ideal for research to discover the mechanisms of injury and for testing vaccines and therapeutics to prevent teratogenesis, fetal and neonatal injury and adverse pregnancy outcomes (e.g., stillbirth or spontaneous abortion). In this review, we emphasize key contributions of the NHP model pre-clinical research for ZIKV, HCMV, HIV, IAV, L. monocytogenes, Ureaplasma species, and GBS. This work represents the foundation for development and testing of preventative and therapeutic strategies to inhibit infectious injury of human fetuses and neonates.
ABSTRACT
Collection of blood samples for research or clinical evaluation is one of the most common procedures performed in nonhuman primates. Several possible methods can be used to obtain samples. In the early days of primate research, manual or physical restraint was used, which was stressful for the animal and risky for the human. As the field developed, chemical immobilization with ketamine or other anesthetics has become the most commonly used method. More recently, training using positive reinforcement has allowed collection of blood samples from unsedated primates that are unrestrained or minimallyrestrained. Elimination of anesthesia reduces risks to the animal. We wanted to determine whether the risks to humans were different between the sedated or unsedated blood collection. We evaluated injury and near-miss reports in conjunction with blood collection data from 2009 to 2019 at the Washington National Primate Research Center, which houses macaques (M. nemestrina, M. mulatta, and M. fasicularis) and squirrel monkeys (S. sciureus), and has housed baboons (Papio sp.) in the past. Injuries associated with sedated blood collection included those occurring during the sedation procedure and recovery as well as those directly associated with blood collection. Injuries associated with unsedated blood collection included those which occurred both during animal training and during blood collection. Overall, 22 human injury exposures and 5 nearmisses were associated with 73,626 blood collection procedures. Based on these numbers, 0.026% of sedated blood collections and 0.116% of unsedated blood collections were associated with exposure incidents. In conclusion, our data indicate a very low risk of exposure associated with blood collection. In this data set, the risk was statistically higher for unsedated animals, but the low number of incidents and the variability in the methods of blood collection make the general applicability of this finding questionable.
ABSTRACT
The studies presented in this work were designed to evaluate the genetic toxicity of methylphenidate hydrochloride (MPH) in non-human primates (NHP) using a long-term, chronic dosing regimen. Thus, approximately two-year old, male rhesus monkeys of Indian origin were orally exposed to MPH diluted in the electrolyte replenisher, Prang, five days per week over a 20-month period. There were 10 animals per dose group and the doses were (1) control, Prang only, (2) low, 0.15 mg/kg of MPH twice per day increased to 2.5mg/kg twice per day and (3) high, 1.5 mg/kg of MPH twice per day increased to 12.5 mg/kg twice per day. Blood samples were obtained from each animal to determine the base-line serum levels of MPH and the major metabolite of MPH in NHP, ritalinic acid (RA). In addition, the base-line frequency of micronucleated erythrocytes (MN-RETs) by flow cytometry, HPRT mutants by a lymphocyte cloning assay, and chromosome aberrations by FISH painting were determined from peripheral blood samples. Once dosing began, the serum levels of MPH and its major metabolite, RA, were determined monthly. The MN-RET frequency and health parameters (CBC, serum chemistries) were also determined monthly. HPRT mutant and chromosome aberration frequencies were measured every three months. CBC values and serum chemistries, with the exception of alanine amino transferase, were within normal limits over the course of drug exposure. The final plasma levels of MPH were similar to those produced by the pediatric dose of 0.3 microg/ml. No significant increases in the frequencies of MN-RETs, HPRT mutants, or chromosome aberrations were detected in the treated animals compared to the control animals over the 20-month exposure period.
Subject(s)
Chromosome Aberrations/chemically induced , Hypoxanthine Phosphoribosyltransferase/genetics , Methylphenidate/pharmacology , Animals , Body Weight/drug effects , Cells, Cultured , Micronucleus Tests , Mutation/genetics , Primates , Tandem Mass SpectrometryABSTRACT
Estrogenic compounds are known to prevent bone loss in ovariectomized adult rats; however, their effects on bone in developing and reproductively-intact rats are less well-understood. In a large multigenerational experiment 0, 2, 10, or 50 ppb ethinyl estradiol (EE) in the diet was fed to intact male and female rats from conception until either weaning, postnatal day 140, or continuously for 2 years. Vertebrae (lumbar and caudal) and femurs were collected from subsets of these animals at necropsy at 48 days, 70 days, 140 days, or 2 years of age and subjected to dual-energy X-ray absorptiometry (DXA) scanning to measure bone mineral density (BMD), bone mineral content (BMC), and bone area. In addition, the length, cross-sectional area, marrow area, and cortical bone area of the femurs were measured directly in all animals at PND 140 and 2 years. Continuous dietary intake of 50 ppb EE decreased body weight by 8-27%. BMD adjusted for body weight was not affected by EE, with the exception of an increase in the caudal vertebrae in males treated with 50 ppb EE. In female rats, continuous treatment with 50 ppb EE decreased length and cross-sectional area of the femur. The length of the femur was decreased in the first two generations following institution of a phytoestrogen-free diet at the initiation of the study in all animals, including controls, but returned to the original length by the third or fourth generation. The cross-sectional area of the femur also varied by generation. In conclusion, a high dose of EE throughout the lifespan resulted in decreased bone size in females, which could reduce the force required to break the bone. Furthermore, dietary changes may have epigenetic effects which persist for multiple generations.
Subject(s)
Bone Density/drug effects , Bone and Bones/drug effects , Ethinyl Estradiol/pharmacology , Absorptiometry, Photon , Animals , RatsABSTRACT
Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD.
Subject(s)
Disease Reservoirs/virology , Hematopoietic Stem Cell Transplantation , Major Histocompatibility Complex , Simian Immunodeficiency Virus/physiology , Transplantation, Haploidentical , Animals , Antiretroviral Therapy, Highly Active , CD8-Positive T-Lymphocytes/immunology , DNA, Viral/metabolism , Macaca mulatta , RNA, Viral/metabolism , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Transplantation, HomologousABSTRACT
Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.
Subject(s)
Abortion, Spontaneous/virology , Stillbirth/veterinary , Zika Virus Infection/veterinary , Zika Virus/physiology , Animals , Female , Kaplan-Meier Estimate , Male , Pregnancy , PrimatesABSTRACT
Ketamine is widely used as a pediatric anesthetic. Studies in developing rodents have indicated that ketamine-induced anesthesia results in brain cell death. Additional studies are needed to determine if ketamine anesthesia results in brain cell death in the nonhuman primate and if so, to begin to define the stage of development and the duration of ketamine anesthesia necessary to produce brain cell death. Rhesus monkeys (N = 3 for each treatment and control group) at three stages of development (122 days of gestation and 5 and 35 postnatal days [PNDs]) were administered ketamine intravenously for 24 h to maintain a surgical anesthetic plane, followed by a 6-h withdrawal period. Similar studies were performed in PND 5 animals with 3 h of ketamine anesthesia. Animals were subsequently perfused and brain tissue processed for analyses. Ketamine (24-h infusion) produced a significant increase in the number of caspase 3-, Fluoro-Jade C- and silver stain-positive cells in the cortex of gestational and PND 5 animals but not in PND 35 animals. Electron microscopy indicated typical nuclear condensation and fragmentation in some neuronal cells, and cell body swelling was observed in others indicating that ketamine-induced neuronal cell death is most likely both apoptotic and necrotic in nature. Ketamine increased N-methyl-D-aspartate (NMDA) receptor NR1 subunit messenger RNA in the frontal cortex where enhanced cell death was apparent. Earlier developmental stages (122 days of gestation and 5 PNDs) appear more sensitive to ketamine-induced neuronal cell death than later in development (35 PNDs). However, a shorter duration of ketamine anesthesia (3 h) did not result in neuronal cell death in the 5-day-old monkey.
Subject(s)
Anesthetics, Dissociative/toxicity , Animals, Newborn/physiology , Excitatory Amino Acid Antagonists/toxicity , Ketamine/toxicity , Neurons/drug effects , Anesthetics, Dissociative/pharmacokinetics , Animals , Autoradiography , Caspase 3/metabolism , Cell Death/drug effects , Fluoresceins , Immunohistochemistry , In Situ Hybridization , In Situ Nick-End Labeling , Ketamine/pharmacokinetics , Macaca mulatta , Mass Spectrometry , Microscopy, Electron , Organic Chemicals , Oximetry , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, N-Methyl-D-Aspartate/drug effects , Reference Standards , Silver StainingABSTRACT
13-cis-retinoic acid (13-cis-RA, isotretinoin) is used to treat severe recalcitrant acne. Other retinoids have adverse effects on bone. Recent studies of human patients treated with 13-cis-RA have had varying results, perhaps because of variability among patients and the lack of control groups. The effects of retinoids have been studied in rodents, but little information is available regarding the effects of clinically relevant retinoid doses as evaluated by use of bone densitometric techniques. We treated rats for 15 or 20 wk with 13-cis-RA, all-trans-RA, or soybean oil (control) by gavage. We used dual-energy X-ray absorptiometry, histomorphometry, and histologic evaluation to evaluate effects on bone. Spontaneous long bone fractures occurred in some rats treated with 15 mg/kg all-trans-RA daily. Bone mineral density, bone mineral content, bone diameter, and cortical thickness of the femur were reduced in rats treated daily with 10 or 15 mg/kg all-trans-RA or 30 mg/kg 13-cis-RA. The lumbar spine was not affected. Although the effects of 13-cis-RA were not as dramatic as those of all-trans-RA, further study of the effects of 13-cis-RA on long bones is warranted.
Subject(s)
Bone Density/drug effects , Isotretinoin/administration & dosage , Isotretinoin/toxicity , Tretinoin/administration & dosage , Tretinoin/toxicity , Absorptiometry, Photon , Administration, Oral , Animals , Bone Resorption/chemically induced , Bone Resorption/metabolism , Bone Resorption/pathology , Dermatologic Agents/administration & dosage , Dermatologic Agents/toxicity , Disease Models, Animal , Female , Humans , Male , Osteoporosis/chemically induced , Osteoporosis/metabolism , Osteoporosis/pathology , Rats , Rats, Sprague-Dawley , Species SpecificityABSTRACT
Genistein has been shown to prevent bone loss in ovariectomized adult rats. However, the effects of genistein on bone in developing and reproductively-intact rats have not been examined. A large multigenerational experiment involved feeding 0, 5, 100, or 500 ppm genistein in the diet to intact male and female rats from conception until either weaning, postnatal day 140, or continuously for 2 years. Vertebrae (lumbar and caudal) were collected from these animals at necropsy at 2 years of age and subjected to dual-energy x-ray absorptiometry (DXA) scanning to measure bone mineral density (BMD), bone mineral content (BMC), and bone area. Femurs were collected, and length, cross-sectional area, and cortical bone area were measured directly. Serum was collected for measurement of pyridinoline (PYD) and alkaline phosphatase (ALP). BMD was not affected by genistein in any phase of the experiment. In female rats treated continuously with genistein, BMC and bone area were reduced in the 500 ppm group compared to the 5 ppm group in the lumbar vertebrae, and in all treatment groups compared to control in the caudal vertebrae. In both males and females treated continuously, the cross-sectional area of the femur was reduced in rats treated with 500 ppm compared to those treated with 5 ppm. In female rats treated continuously, PYD was higher in the 100 and 500 ppm groups than in the 0 and 5 ppm groups. In conclusion, the effects of genistein on reproductively-intact rats were not dramatic. High dose of genistein throughout the lifespan resulted in decreased bone size, which may reduce the force required to break the bone.
Subject(s)
Aging , Bone Density/drug effects , Genistein/pharmacology , Growth Inhibitors/pharmacology , Alkaline Phosphatase/blood , Amino Acids/blood , Animals , Body Weight/drug effects , Bone Density/physiology , Bone Development/physiology , Dose-Response Relationship, Drug , Female , Femur/anatomy & histology , Femur/growth & development , Femur/physiology , Male , Rats , Rats, Sprague-DawleyABSTRACT
This study evaluated the effects of pair-housing on several operant (trained) behaviors in rhesus macaques (Macaca mulatta). Sixteen young, male, individually housed rhesus monkeys (age, 2.5 to 5.5 years) performed a battery of behaviors consisting of motivation (progressive ratio, PR), short-term memory and attention (delayed matching-to-sample, DMTS), color and position discrimination (conditioned position responding, CPR), and learning (incremental repeated acquisition, IRA) tasks. Behavioral assessments occurred 5 days/week, with the PR, IRA, and CPR tasks presented on one test day, and the DMTS task presented on the next test day. Thus, each task was performed two or three days/week. Eight subjects then were pair-housed, while eight age-matched controls remained individually housed. Pair-housed monkeys were separated for behavior testing and feeding but allowed access to each other approximately 20 h/day. The performance of the two groups of monkeys were compared for the 2 months prior to pairing, for a 2-month transition period as the pairs adjusted to the new housing situation, and for a 2-month period after the pairs had been established. Performance of the CPR and IRA tasks did not change over time in either group. For the PR and DMTS tasks, the number of trials completed increased over the course of the study in the controls but not in the pair-housed monkeys. In conclusion, pair-housing monkeys is feasible for studies involving operant behavior testing as a model for a variety of complex brain functions. However, housing condition may affect some test parameters, and this must be taken into consideration during experimental design.
Subject(s)
Animal Husbandry/methods , Behavior, Animal/physiology , Conditioning, Operant/physiology , Housing, Animal , Macaca mulatta , Task Performance and Analysis , Animals , Attention , Color Perception , Learning , Male , Memory, Short-Term , Motivation , Psychomotor Performance , Reproducibility of ResultsABSTRACT
A 2.25-y-old male pigtailed macaque (Macaca nemestrina) was experimentally irradiated and received a bone marrow transplant. After transplantation and engraftment, the macaque had unexpected recurring pancytopenia and dependent edema of the prepuce, scrotum, and legs. The diagnostic work-up included a blood smear, which revealed a trypomastigote consistent with Trypanosoma cruzi, the causative agent of Chagas disease (CD). We initially hypothesized that the macaque had acquired the infection when it lived in Georgia. However, because the animal had received multiple blood transfusions, all blood donors were screened for CD. One male pigtailed macaque blood donor, which was previously housed in Louisiana, was positive for T. cruzi antibodies via serology. Due to the low prevalence of infection in Georgia, the blood transfusion was hypothesized to be the source of T. cruzi infection. The transfusion was confirmed as the mechanism of transmission when screening of archived serum revealed seroconversion after blood transfusion from the seropositive blood donor. The macaque made a full clinical recovery, and further follow-up including thoracic radiography, echocardiography, and gross necropsy did not show any abnormalities associated with CD. Other animals that received blood transfusions from the positive blood donor were tested, and one additional pigtailed macaque on the same research protocol was positive for T. cruzi. Although CD has been reported to occur in many nonhuman primate species, especially pigtailed macaques, the transmission of CD via blood transfusion in nonhuman primates has not been reported previously.
Subject(s)
Blood Transfusion/veterinary , Chagas Disease/veterinary , Immunocompromised Host , Macaca nemestrina/parasitology , Monkey Diseases/parasitology , Trypanosoma cruzi/isolation & purification , Animals , Antibodies, Protozoan/blood , Biomarkers/blood , Chagas Disease/blood , Chagas Disease/immunology , Chagas Disease/transmission , Dose Fractionation, Radiation , Genetic Therapy , Macaca nemestrina/blood , Macaca nemestrina/immunology , Male , Models, Animal , Monkey Diseases/blood , Monkey Diseases/immunology , Stem Cell Transplantation , Transfusion Reaction , Trypanosoma cruzi/immunologyABSTRACT
Thromboelastography is a clinical laboratory test used to assess global hemostasis. With technologic advances and the test's reemergence in human medicine, its utility in veterinary medicine is being explored. Because assays for PT, aPTT, and d-dimers require platelet-poor plasma, whereas thromboelastography is performed on whole blood, thromboelastography provides a more accurate representation of coagulation and allows the identification of hypocoagulable, hypercoagulable, and hyperfibrinolytic states. Conflicting information has been reported about the effects of age and sex on thromboelastog- raphy in humans and animals. Human studies have reported significant effects of age and sex on thromboelastography more often than have animal studies, but few publications are available about thromboelastography in the nonhuman primate and laboratory animal literature. We used a sample of 50 pigtail macaques (Macaca nemestrina) to determine whether age or sex influence thromboelastography values. Of 5 measured and 2 calculated variables produced by thromboelastography, sex had a significant effect only on the lysis-30 parameter, which also showed significant interaction between age and sex; values increased with age in male macaques but decreased with age in female macaques. In addition, we used the data to define reference intervals for thromboelastography parameters in pigtail macaques.
Subject(s)
Blood Coagulation/physiology , Macaca nemestrina/physiology , Thrombelastography/veterinary , Veterinary Medicine/methods , Age Factors , Animals , Female , Male , Reference Values , Sex Factors , Thrombelastography/methods , Thrombelastography/statistics & numerical data , Time FactorsABSTRACT
Dystocia (difficult labor) is an important component of the management of nonhuman primates and results in significant fetal and maternal morbidity and increased use of veterinary resources. Dystocias can arise from abnormalities of the maternal pelvis or fetus or uncoordinated uterine activity. Although risk factors for stillbirths have been established in nonhuman primates, risk factors for dystocias have not. The objective of this study was to determine maternal and fetal risk factors for dystocia in macaques. Retrospective data were collected from 83 pigtailed macaques (Macaca nemestrina) diagnosed with dystocia. The diagnosis of dystocia was made based on clinical or pathologic evidence. Maternal records of age, reproductive history, experimental history, clinical records, and fetal birth weight and any applicable fetal necropsy reports were reviewed. The gestational age of the fetus, the infant's birth weight, total previous births by the dam, and the proportions of both viable delivery (inverse effect) and surgical pregnancy interventions (direct effect) in the dam's history generated a model that maximized the experimental variance for predicting dystocia in the current pregnancy and explained 24% of the dystocia deliveries. The number of total previous births and proportion of previous cesarean sections accounted for the greatest effect. This model can identify individual dams within a colony that are at risk for dystocias and allow for changes in breeding colony management, more intense monitoring of dams at risk, or allocation of additional resources.
Subject(s)
Dystocia/veterinary , Macaca nemestrina , Monkey Diseases/epidemiology , Animals , Dystocia/epidemiology , Female , Fetal Death/epidemiology , Fetal Death/veterinary , Placenta, Retained/epidemiology , Placenta, Retained/veterinary , Pregnancy , Pregnancy Outcome/veterinary , Risk FactorsABSTRACT
Fat embolization (FE), the introduction of bone marrow elements into circulation, is a known complication of bone fractures. Although FE has been described in other animal models, this study represents the first reported cases of FE and bone marrow embolism in nonhuman primates. Histopathologic findings from cynomolgus macaques (Macaca fascicularis) indicated that in all 5 cases, fat and bone marrow embolization occurred subsequent to multiple bone marrow biopsies. In the most severe case, extensive embolization was associated pulmonary damage consistent with acute respiratory distress syndrome. Fat embolism syndrome (FES) is an infrequent clinical outcome of FE and is triggered by systemic biochemical and mechanical responses to fat in circulation. Although clinical criteria diagnostic of FES were not investigated at the time of death, this severe case may represent the fulminant form of FES, which occurs within 12 h after trauma. Bone marrow biopsy as an etiology of FES has been reported only once in humans. In addition, the association of embolization with bone marrow biopsies suggests that nonhuman primates may be a useful animal model of FE. FE and FES represent important research confounders and FES should be considered as a differential diagnosis for clinical complications subsequent to skeletal trauma.