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1.  Mortality in Captive Baboons (Papio spp.): A 23 Year Study 
Journal of medical primatology  2014;43(3):169-196.
Background
We report the causes of mortality for 4,350 captive baboons that died or were euthanized due to natural causes during a 23 year period at the Southwest National Primate Research Center.
Methods
Necropsy records were retrieved and reviewed to determine a primary cause of death or indication for euthanasia. Data was evaluated for morphological diagnosis, organ system and etiology.
Results
The 20 most common morphologic diagnoses accounted for 76% of the cases, including: stillborn (10.8%); colitis (8.6%); hemorrhage (8.4%); ulcer (5.2%); seizures (4.7%); pneumonia (4.2%); inanition (4.1%); dermatitis (3.8%); spondylosis (3.3%); and amyloidosis (3.0%). The digestive system was most frequently involved (21.3%), followed by the urogenital (20.3%), cardiovascular (12.2%), and multisystem disease (10.3%). An etiology was not identified in approximately one third of cases. The most common etiologies were trauma (14.8%), degenerative (9.5%), viral (8.7%), and neoplastic/proliferative (7.0%).
Conclusion
This information should be useful for individuals working with baboons.
doi:10.1111/jmp.12101
PMCID: PMC3989440  PMID: 24483852
Nonhuman primate; Disease; Epidemiology; Cancer; Pathology; Spontaneous; Survey; Age at death; Lifespan; Morbidity
2.  Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease 
PLoS Neglected Tropical Diseases  2016;10(1):e0004302.
Background
Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations.
Methods and Findings
Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications.
Conclusions
Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease.
Author Summary
T. cruzi is the parasite responsible for Chagas disease, a neglected tropical illness, present in endemic and also in non-endemic countries. T. cruzi parasites are spread mainly by a vector’s bite but can also be transmitted by blood transfusion, organ transplant, laboratory accidents, congenitally and by ingestion of contaminated food. Non-human primates that are also predisposed to become infected, live in places where vectors and T. cruzi exist. Similar clinical sequelae are observed in these animals when compared to humans who are infected with T. cruzi. A better understanding of the pathogenesis of T. cruzi-infected non-human primates may bring new advances to understanding human infection. Here, we explored the immunological features of cynomolgus macaques naturally infected by T. cruzi, aiming to contribute to the validation of this species as an appropriate experimental model. Infected animals displayed a similar immunological profile to that observed in humans, with high activity of cytotoxic cells and expansion of macrophages and T-cell subsets. Furthermore, by using bioinformatics tools, we demonstrated that CD14+CD56+ and CD3+HLA-DR+ cells are major determinants to segregate CH from NI group, followed by innate and adaptive cell subpopulations. Altogether, our data suggest that non-human primates are an appropriate model to study Chagas disease.
doi:10.1371/journal.pntd.0004302
PMCID: PMC4726540  PMID: 26808481
3.  Particle-to-PFU Ratio of Ebola Virus Influences Disease Course and Survival in Cynomolgus Macaques 
Journal of Virology  2015;89(13):6773-6781.
ABSTRACT
This study addresses the role of Ebola virus (EBOV) specific infectivity in virulence. Filoviruses are highly lethal, enveloped, single-stranded negative-sense RNA viruses that can cause hemorrhagic fever. No approved vaccines or therapies exist for filovirus infections, and infectious virus must be handled in maximum containment. Efficacy testing of countermeasures, in addition to investigations of pathogenicity and immune response, often requires a well-characterized animal model. For EBOV, an obstacle in performing accurate disease modeling is a poor understanding of what constitutes an infectious dose in animal models. One well-recognized consequence of viral passage in cell culture is a change in specific infectivity, often measured as a particle-to-PFU ratio. Here, we report that serial passages of EBOV in cell culture resulted in a decrease in particle-to-PFU ratio. Notably, this correlated with decreased potency in a lethal cynomolgus macaque (Macaca fascicularis) model of infection; animals were infected with the same viral dose as determined by plaque assay, but animals that received more virus particles exhibited increased disease. This suggests that some particles are unable to form a plaque in a cell culture assay but are able to result in lethal disease in vivo. These results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures.
IMPORTANCE Ebola virus (EBOV) can cause severe hemorrhagic disease with a high case-fatality rate, and there are no approved vaccines or therapies. Specific infectivity can be considered the total number of viral particles per PFU, and its impact on disease is poorly understood. In stocks of most mammalian viruses, there are particles that are unable to complete an infectious cycle or unable to cause cell pathology in cultured cells. We asked if these particles cause disease in nonhuman primates by infecting monkeys with equal infectious doses of genetically identical stocks possessing either high or low specific infectivities. Interestingly, some particles that did not yield plaques in cell culture assays were able to result in lethal disease in vivo. Furthermore, the number of PFU needed to induce lethal disease in animals was very low. Our results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures.
doi:10.1128/JVI.00649-15
PMCID: PMC4468478  PMID: 25903348
4.  Correlation between Presence of Trypanosoma cruzi DNA in Heart Tissue of Baboons and Cynomolgus Monkeys, and Lymphocytic Myocarditis 
Trypanosoma cruzi, the causative agent of Chagas' disease, preferentially infects cardiac and digestive tissues. Baboons living in Texas (Papio hamadryas) and cynomolgus monkeys (Macaca fascicularis) have been reported to be infected naturally with T. cruzi. In this study, we retrospectively reviewed cases of animals that were diagnosed with lymphocytic myocarditis and used a polymerase chain reaction (PCR)-based method (S36/S35 primer set) to amplify T. cruzi DNA from archived frozen and formalin-fixed paraffin-embedded (FFPE) cardiac tissues. We show that the PCR method is applicable in archived frozen and FFPE tissues and the sensitivity is in the femtogram range. A positive correlation between PCR positivity and lymphocytic myocarditis in both baboons and cynomolgus monkeys is shown. We also show epicarditis as a common finding in animals infected with T. cruzi.
doi:10.4269/ajtmh.13-0448
PMCID: PMC3973505  PMID: 24567317
5.  Establishment of a Neonatal Rhesus Macaque Model to Study Mycobacterium tuberculosis Infection 
Summary
Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) with an estimated 8.8 million new TB cases and 1.4 million deaths annually. Tuberculosis is the leading cause of death in AIDS patients worldwide but very little is known about early TB infection or TB/HIV co-infection in infants. A clinically relevant newborn animal model to study TB infection is urgently needed. We have successfully established an aerosol newborn/infant model in neonatal nonhuman primates (NHPs) that mimics clinical and bacteriological characteristics of Mtb infection as seen in human newborns/infants. Further, this model will allow the establishment of a TB coinfection model of pediatric AIDS. Aerosol versus intra broncho-alveolar Mtb infection was studied. Interestingly, 42 days post infection specific lesions were detected suggestive of the classic Ghon focus in human children. Concurrently, specific cellular immune responses developed 4–6 weeks after Mtb infection. Using the enzyme-linked immunospot (ELISPOT) assays, we found that IL-12 production correlated with early Mtb infection lesions seen by routine thoracic radiographs. Overall, this work represents the first example of early Mtb infection of newborn macaques. This study gives us a unique opportunity to further characterize immunopathogenesis and establish a TB/SIV co-infection model for pediatric AIDS.
doi:10.1016/S1472-9792(13)70011-8
PMCID: PMC4051704  PMID: 24388650
TB; rhesus macaque; newborn; Ghon focus; ELISPOT; IL-12
6.  Spontaneous Pathology of the Baboon Endocrine System 
Journal of medical primatology  2009;38(6):383-389.
Background
Study of endocrine pathology in animal models is critical to understanding endocrine pathology in humans.
Methods
We evaluated 434 endocrine-related diagnoses from 4,619 baboon necropsies, established the incidence of spontaneous endocrine pathology, and analyzed the clinical and biochemical data associated with the individual cases.
Results
The most common diagnoses in descending order, were pancreatic islet cell amyloidosis (n=259), ovarian cysts (n=50), pituitary adenoma (n=37), pancreatic islet cell adenoma (n=20), granulosa cell tumor (n=15), thyroid adenoma (n=11), adrenal hyperplasia (n=10), thyroid carcinoma (n=8), and pheochromocytoma (n=6). The incidence of pancreatic islet cell amyloidosis progressively increased with age. Pheochromocytomas were associated with renal and heart failure. The incidence of pancreatic islet cell amyloidosis and adrenal pathology was similar to humans; the incidence of pituitary adenoma and thyroid pathology was lower than in humans.
Conclusions
Endocrine disease in baboons is common and shares clinical and biochemical characteristics with endocrine disease in humans.
doi:10.1111/j.1600-0684.2009.00384.x
PMCID: PMC2783813  PMID: 19793179
Papio; nonhuman primate; thyroid; pancreas; endocrine; disease; cancer
7.  Spontaneous pathology of the common marmoset (Callithrix jacchus) and tamarins (Saguinus oedipus, Saguinus mystax) 
Journal of medical primatology  2009;38(5):347-359.
Background
Marmosets and tamarins are increasingly used in research, but their pathology remains poorly defined compared to old world primates.
Methods
Necropsy records of 129 marmosets and 52 tamarins were reviewed; none were used experimentally.
Results
The most common marmoset lesions were dehydration, emaciation, nephritis, colitis and inanition. The most common tamarin lesions were dehydration, ascites, emaciation and congestive heart failure. Colitis and heart disease were the most common cause of death in marmosets and tamarins, respectively. Immature marmoset and tamarin deaths often occurred within the first month of life. Immature marmosets usually died from inanition, stillbirth and colitis; immature tamarins from atelectasis, stillbirth, heart failure and colitis. Lymphoma was the most common neoplasm for both marmosets and tamarins.
Conclusion
The findings were similar to prior reports with differences in frequency and severity. We report the first case of endometriosis in a marmoset.
doi:10.1111/j.1600-0684.2009.00362.x
PMCID: PMC2740810  PMID: 19522731
nonhuman primate; Callitrichidae; disease; epidemiology; cancer
8.  Trichobezoars in baboons 
Journal of medical primatology  2009;38(5):302-309.
Background
There is little information available concerning trichobezoars in the nonhuman primate literature.
Methods
We evaluated 118 cases of trichobezoar in baboons over a 29 year period at the Southwest National Primate Research Center.
Results
The anatomic locations affected in decreasing order were the stomach, small intestine, cecum, esophagus, and colon. The most common clinical history was weight loss. The most frequent associated pathology included gastrointestinal inflammation and ulceration, emaciation, peritonitis, intussusception, pneumonia, and aspiration. Trichobezoars were the cause of death in 9 baboons and the reason for euthanasia in 12. Females were 2.14 times more likely than males to be affected. The greater the percentage of group housing time, the more likely the baboon was to develop trichobezoars.
Conclusions
The baboon may present a useful model to evaluate the etiology, genetic predisposition, physiopathology, neurobiology, and treatment response of trichobezoars.
doi:10.1111/j.0047-2565.2009.00355.x
PMCID: PMC2754115  PMID: 19457157
Stomach; hairball; trichophagia; trichotillomania; hair pulling; nonhuman primate; Papio
9.  Spontaneous Heart Disease in the Adult Chimpanzee (Pan troglodytes) 
Journal of medical primatology  2008;38(1):51-58.
Background
A high incidence of heart disease, especially idiopathic cardiomyopathy, is seen in chimpanzees (Pan troglodytes).
Methods
We reviewed clinical records and necropsy reports of 87 adult chimpanzees for possible causes of heart disease/idiopathic cardiomyopathy. We examined age, sex, cause of death, weight, diet, environment, infectious diseases, experimental uses, and clinical pathology.
Results
The overall prevalence of heart disease in chimpanzees was 67.81%; the prevalence of idiopathic cardiomyopathy was 51.72%. The prevalence of idiopathic cardiomyopathy was significantly higher in males (60.32%) than females (29.17%, p=0.009). The prevalence of other heart disease was higher in females (25%) than males (12.70%, p=0.165). Heart failure occurred in 47.13% of chimpanzees. Heart disease was the primary cause of death in 34.49% of chimpanzees; 29.88% died of unknown causes.
Conclusions
We found no evidence that diet, environment, viral agents, experimental use or disease exposure contributed to the deaths resulting from idiopathic cardiomyopathy in chimpanzees.
doi:10.1111/j.1600-0684.2008.00307.x
PMCID: PMC2933140  PMID: 18671767
ape; cardiomyopathy; atherosclerosis; arteriosclerosis; nonhuman primate
10.  Spontaneous Squamous Cell Carcinomas in 13 Baboons, a First Report in a Spider Monkey, and a Review of the Nonhuman Primate Literature 
Journal of medical primatology  2009;38(3):175-186.
Background
Squamous cell carcinoma (SCC) is a neoplastic proliferation of epithelial cells undergoing squamous differentiation and represents a diagnostic challenge in nonhuman primates (NHP), especially in baboons with perineal SCC.
Methods
Fourteen SCC (13 baboons, 1 spider monkey) were identified over a 20-year period. A literature search identified 86 additional published cases of spontaneous NHP SCC.
Results
SCC was most commonly reported in macaques, baboons, marmosets, and squirrel monkeys. Metastasis occurred in 23%, of NHP. The most frequently reported primary locations were the oral cavity, integument, esophagus, and cervix-uterus. Perineal SCC occurred mainly in baboons. All reported SCC in marmosets occurred in the head. Nasal cavity SCC was only reported in male marmosets. All reported pulmonary SCC occurred in males, mostly in tree shrews.
Conclusions
SCC is a common neoplasm in NHP and exhibits species differences. NHPs may provide a useful SCC animal model.
doi:10.1111/j.1600-0684.2009.00338.x
PMCID: PMC2919327  PMID: 19220686
Cancer; neoplasm; Papio; skin; oral cavity; esophagus
11.  Fatal Acute Chagas Disease in a Chimpanzee 
Journal of medical primatology  2009;38(4):247-251.
Background
Chagas disease (CD) or American trypanosomiasis is caused by a hemoflagellate protozoan, Trypanosoma cruzi (TC). This organism has been isolated from more than 100 mammalian species and several insect vectors demonstrating a wide host distribution and low host specificity.
Methods
A 23 year old male chimpanzee died acutely and a complete necropsy was performed to evaluate gross and microscopic pathologic changes. After observation of trypanosomal amastigotes in the myocardium, PCR and immunohistochemistry was employed to confirm the diagnosis of TC.
Results
Gross findings were consistent with mild congestive heart failure. Microscopic findings included multifocal myocardial necrosis associated with severe lymphocytic to mixed inflammatory infiltrates, edema, and mild chronic interstitial fibrosis. Multifocal intracytoplasmic amastigotes morphologically consistent with TC were observed in cardiac myofibers. TC was confirmed by PCR and immunohistochemistry.
Conclusion
We report, to the best of our knowledge, the first fatal spontaneous case of TC infection in a chimpanzee.
doi:10.1111/j.1600-0684.2009.00348.x
PMCID: PMC2711217  PMID: 19281482
Ape; nonhuman primate; protozoa; fatal case; Trypanosoma cruzi
12.  Endometrial and cervical polyps in 22 baboons (Papio sp.), 5 cynomolgus macaques (Macaca fascicularis) and one marmoset (Callithrix jacchus) 
Journal of medical primatology  2009;38(4):257-262.
Background
Endometrial and cervical polyps are masses of endometrium or cervical epithelium that bulge into the uterine or cervical lumen. The physiopathology and contributing factors of endometrial polyps development are still unknown.
Methods
Clinical and pathology records of 28 nonhuman primates with histologically confirmed endometrial and cervical polyps were reviewed. Twenty-one baboons with endometrial polyps were evaluated for age at diagnosis; body weight; menstrual cycle length, presence of endometriosis and adenomyosis; and number of offspring, cesarean sections, and stillbirths.
Results
Endometrial polyps in baboons were associated with increased age, decreased menstrual cycle lengths, endometriosis, and decreased parity. No differences were found for weight, adenomyosis, or number of cesarean sections or stillbirths.
Conclusions
Baboons are a promising model for the study of endometrial polyps because of their similarity to humans in both the development of endometrial polyps and association of many of the same risk factors.
doi:10.1111/j.1600-0684.2009.00350.x
PMCID: PMC2729650  PMID: 19281481
endometrium; uterus; mass; cancer; nonhuman primate
13.  Nonspecific Lymphocytic Myocarditis in Baboons Is Associated with Trypanosoma cruzi Infection 
Non-specific lymphocytic myocarditis (NLM) is frequently observed in baboons within the endemic range of Trypanosoma cruzi. We sought to determine whether T. cruzi infection is a cause of baboon NLM. We evaluated serial histologic sections of cardiac muscle, blood cultures, immunohistochemistry, serology, polymerase chain reaction, and clinical pathology from 31 baboons with NLM to determine whether T. cruzi infection is associated with NLM. Eleven baboons with no evidence of T. cruzi infection by serology and no NLM were used as controls. Seropositivity for T. cruzi was 45% in baboons with NLM compared with a 2–3% colony prevalence. NLM lesion severity was significantly higher in seropositive than seronegative baboons with NLM. NLM was significantly more common in older baboons. No statistical association between NLM and sex, weight, or clinical pathology was found. These results suggest an association between NLM and T. cruzi infection in the baboon.
PMCID: PMC2740900  PMID: 19635876
14.  Polymerase Chain Reaction Detection of Trypanosoma cruzi in Macaca fascicularis Using Archived Tissues 
This study describes conventional and real-time polymerase chain reaction (PCR) methods developed to detect and quantify Trypanosoma cruzi DNA in cynomolgus monkeys (Macaca fascicularis) using formalin-fixed paraffin-embedded blocks archived for periods of up to 6 years. The highest concentration of T. cruzi DNA was found in the myocardium, urinary bladder, stomach, lymph node, adrenal gland, and colon. The concentration of T. cruzi DNA detected in cardiac tissues was 10–100-fold greater than found elsewhere; the mean concentrations of T. cruzi DNA in non-cardiac tissues were otherwise comparable. Trypanosoma cruzi DNA was amplified from cerebrum but not cerebellum or kidney. Successful use of DNA from formalin-fixed, paraffin-embedded blocks is important because most pathology laboratories routinely archive wax blocks. This archived resource can be used for further studies on the prevalence of this disease.
PMCID: PMC2740910  PMID: 19635875
15.  Neoplasia in the Chimpanzee (Pan spp.) 
Journal of medical primatology  2009;38(2):137-144.
Background
Chimpanzees have over 98% genomic sequence homology with humans and may have a similar host response to malignancy. There is minimal information concerning cancer in the chimpanzee and such information would be valuable to individuals caring for and using them for research.
Methods
Spontaneous neoplasia that was documented in two chimpanzee colonies and in the literature were evaluated statistically.
Results
In all, 105 spontaneous and 12 experimental neoplasms were diagnosed. Seventy-four spontaneous tumors occurred in females, 24 in males, and 7 in animals of undetermined sex. Of the spontaneous tumors 89 were benign, 14 were malignant, and 2 were undetermined.
Neoplasia was most common in the urogenital system in females.
Conclusions
Neoplasia is not uncommon in the chimpanzee, is generally benign, and occurs primarily in the urogenital system in females.
PMCID: PMC2893876  PMID: 19367738
Ape; nonhuman primate; cancer; tumor; disease; leiomyoma
16.  Gastrointestinal Stromal Tumors in a Baboon, a Spider Monkey and a Chimpanzee and a Review of the Literature 
Journal of medical primatology  2009;38(3):199-203.
Background
Gastrointestinal stromal tumors (GISTs) are believed to originate from the intestinal pacemaker cells (interstitial cells of Cajal) or their progenitor cells. Spontaneous tumors have been reported in dogs, horses, rhesus, and a chimpanzee and they have been produced experimentally in mice and rats. GISTs represent a diagnostic challenge because they cannot be differentiated from nonlymphoid mesenchymal tumors without using human c-kit (CD117) immunohistochemistry.
Methods
Three neoplasms were incidental findings at necropsy in the stomachs of a baboon and a spider monkey and in the rectum of a chimpanzee.
Results
The GISTs were initially diagnosed grossly and histologically with hematoxylin and eosin as leiomyomas. Immunohistochemical analysis revealed all three were c-kit (CD117) positive.
Conclusions
These are the first reports of GISTs in the baboon and spider monkey and the second in a chimpanzee. The occurrence of GISTs in nonhuman primates may provide a unique opportunity to study these tumors.
doi:10.1111/j.1600-0684.2009.00339.x
PMCID: PMC2887287  PMID: 19220684
Cancer; neoplasm; nonhuman primate; Papio anubis; Ateles paniscus; Pan troglodytes; interstitial cells of Cajal
17.  Natural Chagas Disease in Four Baboons 
Journal of medical primatology  2008;38(2):107-113.
Background
Chagas disease is common in Central and South America and the southern United States. The causative agent is Trypanosoma cruzi (T cruzi, Order Kinetoplastida, Family Trypanosomatidae), a kinetoplastid protozoan parasite of humans and other vertebrates. It is a serious public health issue and the leading cause of heart disease and cardiovascular death in Central and South America. In 1984 a colony baboon was discovered to be infected with T cruzi.
Methods
Since the initial diagnosis was made by microscopic observation of the amastigote forms of T. cruzi in myocardial fibers, T. cruzi amastigotes have been identified in three additional baboons.
Results
The primary findings were similar in all four baboons and were congestive heart failure with edema of dependent areas, hydrothorax, hydropericardium, and multifocal to diffuse lymphoplasmacytic myocarditis.
Conclusions
A baboon animal model of Chagas disease could contribute significantly to the development of therapies for the disease in humans.
doi:10.1111/j.1600-0684.2008.00308.x
PMCID: PMC2884297  PMID: 18671766
nonhuman primate; protozoa; animal model; heart; Trypanosoma cruzi
18.  Primary hepatic neuroendocrine carcinoma in a baboon (Papio sp.) 
Journal of medical primatology  2008;38(1):23-26.
Background
Primary neuroendocrine carcinomas of the liver have rarely been reported in humans and domestic animals, but not in non-human primates.
Methods
We describe the morphologic and immunohistochemical features of a primary hepatic neuroendocrine carcinoma found in a 29-year-old female baboon.
Results and conclusions
The neoplasm was characterized by multiple solid nodules that were multifocally distributed in the liver. Metastases were not observed. Histologically, the neoplasm was composed of cords and nests of epithelial cells arranged in a neuroendocrine pattern, occasionally forming glandular and rosette-like structures. On immunohistochemical evaluation, the neoplastic cells were immunopositive for pancytokeratin, chromogranin A, neuron-specific endolase, and synaptophysin and were negative for vimentin, S100 protein, glucagon, and insulin.
doi:10.1111/j.1600-0684.2008.00304.x
PMCID: PMC2758419  PMID: 18715267
Endocrine; liver; non-human primate; tumor
20.  Stillbirths in Macaca fascicularis 
Journal of medical primatology  2008;37(4):169-172.
Background
Stillbirths in nonhuman primates are a major problem and represent failure of the maternal-fetal-placental unit to maintain normal relationships due to various endogenous, undetermined, or environmental factors.
Methods
Records of 236 stillborns and their dams in a Macaca fascicularis colony during a 7-year period were reviewed retrospectively.
Results
The 7-year stillbirth incidence was 11.99% (236 stillbirths, 1,968 live births). Most (61.02%, n=144) were of undetermined etiology. Fetal causes included trauma (22.46%, n= 53), fetal pneumonia (0.85%, n=2) and congenital anomalies (0.42%, n=1). Maternal causes included dystocia (9.75%, n=23), placental abruption (0.85%, n=2), and uterine rupture (0.42 %, n=1). Forty-nine placentas were available for histologic evaluation; there was placentitis in five and necrosis in five. Most stillbirths occurred close to term. First stillbirths usually occurred in 8- to 12-year-old animals during the first six pregnancies.
Conclusions
Most stillbirths were of undetermined etiology. Fetal trauma was the most common cause.
doi:10.1111/j.1600-0684.2007.00275.x
PMCID: PMC2574872  PMID: 18194223
Stillborn; reproduction; cynomolgus; fetus; placenta; dystocia; nonhuman primate
21.  Analysis of Prostate-Specific Antigen Transcripts in Chimpanzees, Cynomolgus Monkeys, Baboons, and African Green Monkeys 
PLoS ONE  2014;9(4):e94522.
The function of prostate-specific antigen (PSA) is to liquefy the semen coagulum so that the released sperm can fuse with the ovum. Fifteen spliced variants of the PSA gene have been reported in humans, but little is known about alternative splicing in nonhuman primates. Positive selection has been reported in sex- and reproductive-related genes from sea urchins to Drosophila to humans; however, there are few studies of adaptive evolution of the PSA gene. Here, using polymerase chain reaction (PCR) product cloning and sequencing, we study PSA transcript variant heterogeneity in the prostates of chimpanzees (Pan troglodytes), cynomolgus monkeys (Macaca fascicularis), baboons (Papio hamadryas anubis), and African green monkeys (Chlorocebus aethiops). Six PSA variants were identified in the chimpanzee prostate, but only two variants were found in cynomolgus monkeys, baboons, and African green monkeys. In the chimpanzee the full-length transcript is expressed at the same magnitude as the transcripts that retain intron 3. We have found previously unidentified splice variants of the PSA gene, some of which might be linked to disease conditions. Selection on the PSA gene was studied in 11 primate species by computational methods using the sequences reported here for African green monkey, cynomolgus monkey, baboon, and chimpanzee and other sequences available in public databases. A codon-based analysis (dN/dS) of the PSA gene identified potential adaptive evolution at five residue sites (Arg45, Lys70, Gln144, Pro189, and Thr203).
doi:10.1371/journal.pone.0094522
PMCID: PMC3986117  PMID: 24732672
22.  Pathology of spontaneous air sacculitis in 37 baboons and 7 chimpanzees and a brief review of the literature 
Journal of Medical Primatology  2012;41(4):266-277.
Background
Air sacculitis is an important clinical condition in non-human primates.
Methods
We evaluated 37 baboons and 7 chimpanzees with spontaneous air sacculitis submitted to pathology over a 20 year period.
Results
Air sacculitis was observed almost exclusively in males. Common reported signs were halitosis, coughing, nasal discharges, depression, anorexia, and weight loss. Gross lesions included thickened air sacs and suppurative exudate lining the walls. Microscopic lesions included marked epithelial hyperplasia or hypertrophy, necrosis, fibrosis, cellular infiltrates, and bacterial colonies. Mixed bacterial infections were more common than infections by single species of bacteria. Streptococcus sp. was the most frequent bacteria isolated in both baboons and chimpanzees.
Conclusions
This is the first report describing the gross and microscopic lesions of air sacculitis in chimpanzees. The preponderance of males suggests a male sex predilection in baboons.
doi:10.1111/j.1600-0684.2012.00547.x
PMCID: PMC3402580  PMID: 22765381
Air sac; Airsacculitis; Pan; Papio; Non-human primate
23.  The Length of the Barrett's Mucosa in Baboons, Revisited 
Anticancer research  2012;32(8):3115-3118.
Background
Chewing of regurgitated food with rumination elicits, gastroesophageal reflux (GER) in baboons. Protracted reflux transforms the distal multilayered squamous cell-lined epithelium into columnar-lined mucosa, with mucus-producing glands having interspersed oxyntic glands. In humans, this histological constellation is called Barrett's mucosa type 2 (BMT2).
Materials and Methods
The distal esophagus together with the proximal stomach was removed en bloc, at autopsy, from 35 adult baboons. Longitudinal sections were stained with toluidine blue, a stain that permits easy discrimination between parietal and chief gastric glands. Using a calibrated ocular scale, the length of the BMT2 was assessed in all 35 baboons.
Results
The mean length of the BMT2 was 9.80 mm (range 1.0 mm–40.2 mm).
Conclusion
BMT2 in baboons is an integrated part of the natural phenomenon of mucosal adaptation to daily regurgitation of gastric acid into the distal esophagus (natural GER), whereas BMT2 in humans might reflect an evolutionary atavism in the esophagus, triggered by a non-physiological disorder (pathological GER). The baboon offers a suitable model to monitor the series of histological events that take place in the distal esophagus under the influence of protracted GER.
PMCID: PMC3468325  PMID: 22843881
Barrett's mucosa; esophagus; baboon; reflux; mucus; metaplasia
24.  The Ontogeny of the Endocrine Pancreas in the Fetal/Newborn Baboon 
The Journal of endocrinology  2012;214(3):289-299.
Background
Erratic regulation of glucose metabolism including hyperglycemia is a common condition of premature infants and is associated with increased morbidity and mortality.
Objective
To examine histological and ultra-structural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons.
Methods
Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140dGA, or 175dGA. Eight animals were delivered at term (185dGA); half were fed for 5d. Seventy-three non-diabetic adult baboons were used for comparison. Pancreatic tissue was studied utilizing light microscopy, confocal imaging and electron microscopy.
Results
The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of α-β-δ-cell type were similar within each fetal and newborn GA (NS), but were higher than the adults (P<0.05) regardless of GA. The ratio of β-cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons who survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared to their counterparts euthanized at birth (P=0.01). Endocrine cells were found amongst exocrine ductal and acinar cells in 125,140 and 175dGA fetuses. Subpopulation of cells that co-expressed trypsin and glucagon/insulin show the presence of cells with mixed endo-exocrine lineage in fetuses.
Conclusions
The fetal endocrine pancreas has no prevalence of a of α-β-δ-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long term implications.
doi:10.1530/JOE-12-0070
PMCID: PMC3686495  PMID: 22723715
Insulin; glucagon; fetus; islet cells; primates
25.  Craniorachischisis and Omphalocele in a Stillborn Cynomolgus Monkey (Macaca fascicularis) 
Nonhuman primates have been a common animal model to evaluate experimentally-induced malformations. Reports on spontaneous malformations are important in determining the background incidence of congenital anomalies in specific species and in evaluating experimental results. Here we report on a stillborn cynomolgus monkey (Macaca fascicularis) with multiple congenital anomalies from the colony maintained at the Southwest National Primate Research Center at the Southwest Foundation for Biomedical Research, San Antonio, Texas. Physical findings included low birth weight, craniorachischisis, facial abnormalities, omphalocele, malrotation of the gut with areas of atresia and intussusception, a Meckel diverticulum, arthrogryposis, patent ductus arteriosus, and patent foramen ovale. The macaque had normal male external genitalia, but undescended testes. Gestational age was unknown but was estimated from measurements of the limbs and other developmental criteria. Although cytogenetic analysis was not possible due to the tissues being in an advanced state of decomposition, array Comparative Genomic Hybridization analysis using human bacterial artificial chromosome clones was successful in effectively eliminating aneuploidy or any copy number changes greater than approximately 3–5 Mb as a cause of the malformations. Further evaluation of the animal included extensive imaging of the skeletal and neural tissue defects. The animal’s congenital anomalies are discussed in relation to the current hypotheses attempting to explain the frequent association of neural tube defects with other abnormalities.
doi:10.1002/ajmg.a.33627
PMCID: PMC3678351  PMID: 21567905
neural tube defects; schisis association; macaque; cynomolgus monkey; non-human primate; congenital defects; malformations

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