Metastatic Hepatocellular Carcinoma in a Juvenile Rhesus Macaque (Macaca mulatta)

Neoplasia in juvenile (younger than 5 y) rhesus macaques has been estimated to represent only approximately 1.4% of all occurrences of spontaneous neoplasia. Here we report an unusual case of a 3.75-y-old primiparous female rhesus macaque that was euthanized due to poor prognosis associated with progressive anemia, marked hepatomegaly, and radiographic evidence of metastatic neoplasia. Postmortem examination revealed an invasive, hemorrhagic hepatic mass that effaced approximately 70% of the liver parenchyma and had evidence of metastatic spread to multiple abdominal organs, the lungs, and the pituitary gland. Neoplastic polygonal cells lined large necrohemorrhagic cavities and exhibited marked anisocytosis and anisokaryosis, with frequent multinucleate cells. There was no desmoplasia associated with the primary neoplasm or metastases. Immunohistochemical studies revealed the neoplastic cells to be diffusely reactive with pancytokeratin, cytokeratin 7, and cytokeratin 8/18 antibodies and rarely reactive with carcinoembryonic antigen antibodies. The cells did not react with vimentin, S100, CD31, or factor VIII antibodies. Tumor morphology and immunophenotype led to the diagnosis of anaplastic hepatocellular carcinoma. This report represents the first known case of metastatic liver neoplasia in a rhesus macaque. The young age of this animal and the aggressive nature of the neoplasm are highly unusual and reminiscent of adolescent onset hepatocellular carcinoma in humans.Abbreviations: CK, cytokeratin; HCC, Hepatocellular carcinomaNeoplasia in juvenile rhesus macaques (Macaca mulatta) is extremely uncommon.^17,18 In a recent review of spontaneous neoplasia in 2 colonies of rhesus macaques, animals younger than 5 y represented only 1.4% of the total number of cases, and primary hepatic tumors were uncommon.¹⁸ All 5 of the cases detected among 2660 macaques involved animals between 14 and 26.8 y of age, and none had evidence of metastasis. Primary hepatic tumors appear to be similarly infrequent occurrences in other nonhuman primates, with the notable exception of prosimians, in which tumors arising from the liver are common spontaneous neoplasms.^3,15,17,18 Malignant liver tumors account for only 1% of pediatric tumors in humans.^5,7,12 Approximately 80% of these are hepatoblastomas—neoplasms arising from liver progenitor cells—and hepatocellular carcinoma (HCC) represents the second most frequent diagnosis.^5,7,12The medicine department of the California National Primate Research Center evaluated a 3.75-y-old, sexually mature, female rhesus macaque for rapidly progressive disease associated with a hepatic mass. Anaplastic HCC with extensive metastasis was diagnosed after postmortem examination. The current report describes the clinical progression of disease, the gross and microscopic pathology of the affected macaque, and the immunohistochemical characterization of the neoplasm.     

MamuSNP: a resource for Rhesus Macaque (Macaca mulatta) genomics

We developed a novel method for identifying SNPs widely distributed throughout the coding and non-coding regions of a genome. The method uses large-scale parallel pyrosequencing technology in combination with bioinformatics tools. We used this method to generate approximately 23,000 candidate SNPs throughout the Macaca mulatta genome. We estimate that over 60% of the SNPs will be of high frequency and useful for mapping QTLs, genetic management, and studies of individual relatedness, whereas other less frequent SNPs may be useful as population specific markers for ancestry identification. We have created a web resource called MamuSNP to view the SNPs and associated information online. This resource will also be useful for researchers using a wide variety of Macaca species in their research.     

Intracranial Meningioma with Ophthalmoplegia in a Rhesus Macaque (Macaca mulatta)

A 21-y-old female rhesus macaque presented with signs of internal and external ophthamoplegia, including anisocoria and ptosis. Ophthalmoplegia is the paralysis or weakness of one or more intraocular or extraocular muscles that control the movement of eye; this condition can be caused by neurologic or muscle disorders. The macaque was euthanized due to progression of clinical symptoms, and postmortem gross examination revealed a mass at the base of the brain attached to the meninges. Histopathologic examination led to the diagnosis of intracranial meningioma. Here we describe a case of intracranial meningioma with internal and external ophthalmoplegia in a rhesus macaque (Macaca mulatta).Meningioma is a tumor that develops in the meninges, including the dura mater, arachnoid mater, and pia mater, all of which surround the brain and spinal cord. In humans, meningioma is the most frequently encountered primary intracranial neoplasia and accounts for approximately 35% of all reported primary brain tumors in the United States.^5,7 Clinical manifestations are dependent on the size and location of the tumor.^3,23 To our knowledge, only 3 cases of naturally occurring meningioma in nonhuman primates have been reported; these cases affected 2 baboons and 1 collared brown lemur.^17,19,21 The meningiomas of 2 of these previous cases were described only briefly as part of a disease survey of neoplasia in 100 free-ranging baboons and a captive prosimian population.^17,21 The third report focused on the pathologic features of the meningioma described with no mention of the clinical signs in the baboon, although its location was similar to that of the case we describe here.¹⁹In the current case report, we describe the clinical manifestations, postmortem examination, and diagnosis of an intracranial meningioma in a rhesus macaque (Macaca mulatta).     

Brain Abscess in a Rhesus Macaque (Macaca mulatta) with a Cephalic Implant

We report a case of brain abscess after craniotomy and the placement of a recording chamber for electrophysiologic records in an adult rhesus macaque (Macaca mulatta) enrolled in visual research. Approximately 2 wk after surgery, the macaque presented with nonspecific gastrointestinal signs and showed no evidence of fever, neurologic deficits, increased intracranial pressure, suggestive alterations in the CBC, or abnormal changes in the recording chamber. The macaque responded to symptomatic and antibiotic treatment and showed no behavioral or abnormal clinical signs for 3 wk before collapsing suddenly. The macaque was euthanized, and pathologic evaluation revealed a large brain abscess immediately under the original craniotomy.Brain abscess is a serious, potentially fatal condition that can arise from direct implantation of an infectious organism (for example, trauma, wound or surgical complication), local extension from an adjacent structure (for example, infection of the cribriform plate, inner ear, paranasal sinus), or hematogenous spread (usually from a primary site in the heart, lungs or tooth extraction by bacterial embolism).^9,14 In humans, most brain abscesses are due to direct or indirect cranial infection from the paranasal sinus, middle ear, or teeth. An increasing proportion is secondary to head trauma or complications from neurosurgeries, whereas as many as 20% to 30% of cases have no obvious or identified cause.⁶ The condition is relatively uncommon in nonhuman primates because of the lack of foci of infection that can lead to direct extension to the brain.¹⁹ The hematogenous spread of bacteria or fungi is considered the most common route,² whereas brain abscesses from direct implantation of a pathogen are seldom reported in the literature despite the numerous nonhuman primates involved in neuroscience research and undergoing regular electrophysiologic recordings in the brain. Most importantly, a brain abscess can be difficult to diagnose, given its nonspecific and variable presentation in both humans and nonhuman primates.^13,19Here we describe the clinical case of an adult rhesus macaque (Macaca mulatta) involved in neuroscience research who presented with nonspecific gastrointestinal signs 2 wk after cephalic implantation and craniotomy surgery. The macaque responded to symptomatic treatment, but the condition recurred several weeks later and led to acute circulatory shock. During necropsy, the condition was diagnosed as a brain abscess.     

Sources of Acoustic Variation in Rhesus Macaque (Macaca mulatta))Vocalizations

All species in the genus Macaca produce a set of harmonically rich vocalizations known as “coos”. Extensive acoustic variation occurs within this call type, a large proportion of which is thought to be associated with different social contexts such as mother-infant separation and the discovery of food. Prior studies of these calls have not taken into account the potential contributions of individual differences and changes in emotional or motivational state. To understand the function of a call and the perceptual salience of different acoustic features, however, it is important to determine the different sources of acoustic variation. I present data on the rhesus macaques' (M. mulatta) coo vocalization and attempt to establish some of the causes of acoustic variation. A large proportion of the variation observed was due to differences between individuals and to putative changes in arousal, not to differences in social context. Specifically, results from a discriminant-function analysis indicated that coo exemplars were accurately assigned to the appropriate individual, but vocal “signatures” were more variable in some contexts than in others. Moreover, vocal signatures may not always be reliable cues to caller identity because closely related individuals sound alike. Rhesus macaque coos evidently provide sufficient acoustic information for individual recognition and possibly kin recognition, but are unlikely to provide sufficient information about an external referent.     

Meningoencephalitis Due to Listeria monocytogenes in a Pregnant Rhesus Macaque (Macaca mulatta)

We here report a spontaneous case of meningoencephalitis due to Listeria monocytogenes in an adult primiparous rhesus macaque (Macaca mulatta) during an outbreak of listeriosis in an outdoor enclosure. Clinical signs included tremors, abnormal posture, and altered mental status. Hematology and analyses of cerebrospinal fluid were consistent with bacterial infection. Pure cultures of L. monocytogenes were recovered from the placenta–abortus, cerebrospinal fluid, and brain tissue. The macaque did not respond to treatment and was euthanized. Histopathologic examination of the brain revealed acute meningoencephalitis. This case represents an unusual clinical and pathologic presentation of listeriosis in a nonhuman primate in which the dam and fetus both were affected.Listeria monocytogenes is a ubiquitous, facultative anaerobic, intracellular gram-positive coccobacillus. This bacterium is found in diverse environments including (but not limited to) soil, water, plant matter, food items, and the intestinal tract of mammalian hosts.^15,18 The organism is environmentally resistant, being able to survive in dried media for several months and in moist soil for up to a year.¹⁵ L. monocytogenes is the causative agent of listeriosis, a bacterial infection that has a worldwide distribution and affects a wide range of mammals and birds, including human beings.In people, L. monocytogenes is a relatively uncommon foodborne pathogen; its abilities to survive food processing and grow in cold conditions allow it to persist in appropriately stored or refrigerated foods.² In people, listeriosis occurs both sporadically and as large outbreaks,¹⁸ generally comprising 3 separate syndromes with clinical manifestations ranging from mild to life-threatening.³⁵ The most common form is seen in immunocompetent, nonpregnant adults as a febrile gastroenteritis.^2,18,21 The other 2 forms, which occur in fetuses and immunocompromised patients, are more severe.^19,21 In pregnant women, maternal listeriosis is asymptomatic or causes mild, flu-like symptoms, but the bacterium''s ability to cross the placenta and the blood–brain barrier of the fetus results in neonatal septicemia, meningitis, abortion, and stillbirth.¹⁶ In elderly and immunocompromised patients, septicemia and meningoencephalitis are life-threatening manifestations of literiosis.²⁶ The worldwide case fatality rate varies widely among countries, sometimes exceeding 50% despite what is considered to be appropriate antibiotic therapy.¹⁸ In 2009, the Centers for Disease Control reported 524 cases of listeriosis in the United States, which were associated with a 19% resulting in death.⁴In ruminants, listeriosis is also known as ‘circling disease’ and ‘silage disease.’^8,18,21 Foodborne infection with L. monocytogenes is well described, and many studies have shown that spoiled silage may be a source of listeria outbreaks.^8,18 Rhombencephalitis and diffuse meningoencephalitis are the most recognized forms of the infection in ruminants; sporadic abortion is reported also.²² Clinical signs of listeria encephalitis in cattle, sheep, and goats are characterized by unilateral or bilateral brainstem dysfunction and cranial nerve deficits. In sheep and goats, the course of the disease is acute, but the disease in cattle has a more chronic progression, with neurologic manifestations that can last 4 to 14 d.^1,22In rabbits, infection with L. monocytogenes is characterized by abortion in pregnant does or sudden death; neurologic signs are rare.¹ In poultry, an acute form with septicemia and sudden death occurs in adults, in contrast to a subacute–chronic form, with encephalitis, in the young.⁶The literature on L. monocytogenes in nonhuman primates is sparse^5,11,17,33 and more recently limited to experimental infection of pregnant animals. In pregnant rhesus macaques (Macaca mulatta), experimental infection during the last trimester of gestation can cause stillbirth with no other clinical signs.^23,24 In our colony, however, infection with L. monocytogenes is endemic. Every year, several spontaneous abortions or stillbirths in our outdoor colony are caused by infection of the dam with this organism. Culture of L. monocytogenes from both the abortus–fetus and placenta are well documented. As described in the literature,^23,24 the dams in our colony do not demonstrate any clinical signs prior to the abortion or stillbirth.During the winter to spring of 2011, one of our outdoor housing enclosures experienced an outbreak of listeriosis. This outside corral housed 100 rhesus macaques in a social group that included 42 reproductive females. Of these reproductive females, 37 (88%) were confirmed pregnant by abdominal palpation or ultrasonography or both. From January 2011 to May 2011, 19 (51%) stillbirths and neonatal deaths (in infants younger than 3 d) were reported in this enclosure; 13 (68%) of these tissues (placenta, 3; fetal lungs, 8; fetal peritoneum, 2) were culture-positive for L. monocytogenes. In all cases except the one presented here, the dam did not manifest any clinical signs prior to or after the delivery of a stillborn or premature birth with neonatal death.Here we describe an unusual case of listeriosis in a primiparous pregnant female rhesus macaque that manifested severe neurologic impairment and intrautero death of the fetus.     

Efficacy of Antibiotic-Impregnated Polymethylmethacrylate Beads in a Rhesus Macaque (Macaca mulatta) with Osteomyelitis

Here we describe the successful surgical implementation of antibiotic-impregnated polymethylmethacrylate beads in a rhesus macaque (Macaca mulatta) with marked osteomyelitis. The macaque presented to the veterinary clinic with grossly contaminated bite wounds in the left ankle secondary to conspecific trauma. Radiographic findings were highly suggestive of osteomyelitis. Additional differential diagnoses included bony infarct, fracture, and cellulitis. In light of the location of the lesion and extensive tissue trauma, the animal had a poor prognosis. Systemic, broad-spectrum antibiotics were instituted. After 2 wk of care, lesions did not respond to empirical therapies. On consultation, a veterinary orthopedic surgeon at another facility recommended placement of antibiotic-impregnated polymethylmethacrylate beads at the sites of osteomyelitis. The animal underwent minor surgery in which beads were introduced into the wound. The monkey had a positive response to therapy. The animal regained full function and was returned to outdoor social housing. Veterinarians are encouraged to consider using antibiotic-impregnated polymethylmethacrylate beads when treating osteomyelitis in other nonhuman primates and in other traditional laboratory animal species.Rhesus macaques can be aggressive, and mild to marked trauma can result from agonistic social encounters.⁶ The AAALAC-accredited California National Primate Research Center houses more than 4000 rhesus macaques (Macaca mulatta) in large outdoor social corrals. The incidence of animals presenting to the center''s veterinary hospital with traumas requiring sutures or amputation of digits ranges from 5% to 9% annually. Bite wounds predominate and frequently involve extremities (tail tips and digits). Open wounds place animals at risk for development of acute or chronic infections, including osteomyelitis.^8,9,11,21 Bacterial contaminants reflect the presence of oral flora secondary to characteristic wounding (for example, Bacteroides spp., coagulase-positive Staphlococcus spp., and Eicinella spp.).Clinical management of osteomyelitis is challenging. The standard of care is based on irrigation of the wound, debridement of necrotic tissues, and administration of systemic antibiotics. Efficacy of systemic antibiotic therapy can be compromised due to poor tissue perfusion and compromised vasculature. Regimens for local administration of antibiotics are being developed continually to improve orthopedic wound management.^{5,8,9,11,19,21,24,26} Antibiotic-impregnated polymethylmethacrylate (bone cement) is used in human and veterinary orthopedic surgery to provide high, localized concentrations of antibiotics in high-risk, poorly vascularized wounds.Few cases of osteomyelitis have been reported in nonhuman primates, and even fewer reports reflect successful management of such conditions.^{4,23,25,27,28} Here we document the successful clinical use of antibiotic-impregnated polymethylmethacrylate beads to treat osteomyelitis in a laboratory-housed rhesus macaque.     

Granuloma Due to Oxidized Regenerated Cellulose in an Aged Rhesus Macaque (Macaca mulatta)

Bioabsorbable hemostatic agents such as oxidized regenerated cellulose are widely used to control intraoperative diffuse capillary bleeding. Compared with electrocautery or ligation, oxidized regenerated cellulose has the advantage of controlling bleeding without occluding the vessel lumen or causing thermal injuries to adjacent tissue. Although the manufacturer recommends removal of the material once hemostasis is achieved, oxidized regenerated cellulose is a bioabsorbable hemostatic agent and is often left in the surgical bed to prevent subsequent bleeding after surgical closure. However, noninvasive imaging techniques have revealed granulomatous foreign-body reactions that mimic infection or tumor recurrence. We present a case report of sterile peritonitis and granuloma formation secondary to the presence of oxidized regenerated cellulose after intestinal resection to excise a colonic adenocarcinoma in an aged rhesus macaque.Bioabsorbable hemostatic agents such as oxidized regenerated cellulose (for example, Surgicel) are widely used to control intraoperative diffuse capillary bleeding. Compared with electrocautery or ligation, oxidized regenerated cellulose has the advantage of controlling bleeding without occluding the vessel lumen or causing thermal injuries to adjacent tissue.¹⁶Oxidized regenerated cellulose is formed by dissolving the α-cellulose of decomposed wood pulp in an alkaline solution and subsequently regenerating it as a continuous fiber. This fiber is then woven into a gauze and oxidized.^17,22 Oxidized regenerated cellulose is supplied as a substrate that is flexible, malleable, and trimable.¹⁶The mechanism of hemostasis of oxidized regenerated cellulose is reportedly associated with its caustic activity.² The oxidation of cellulose produces a low-pH organic acid that reacts with blood, thus forming an artificial clot and causing platelet aggregation.¹⁸Although the manufacturer recommends the removal of oxidized regenerated cellulose once hemostasis is achieved,⁸ the product, a bioabsorbable hemostatic agent, is often left in situ within the surgical bed to prevent bleeding after surgical procedures. The biodegradation and elimination of oxidized regenerated cellulose from the tissue occurs in 2 phases.¹⁴ Polyanhydroglucuronic acid, the major functional unit of oxidized regenerated cellulose, is readily soluble. This acid is degraded extracellulary and systematically cleared from the system approximately 18 h after implantation.^13,14 The remaining fibrous residue, however, requires macrophage phagocytosis for clearance and can be observed within macrophages for at least 48 h after implantation.¹³ Unfortunately, these fibrous residues have a prolonged degradation, and their persistence for as long as 7 mo after surgery has been confirmed histologically.⁷Despite the biocompatibility of oxidized regenerated cellulose, granulomatous foreign-body reactions that imitate infection or tumor recurrence have been revealed by using noninvasive imaging techniques.^{1,11,12,15,17,18,22} Here we describe a case of peritonitis and granuloma formation secondary to the presence of oxidized regenerated cellulose after an intestinal resection to excise a colonic adenocarcinoma in an aged rhesus macaque.     

Self-Injurious Behavior Secondary to Cytomegalovirus-Induced Neuropathy in an SIV-Infected Rhesus Macaque (Macaca mulatta)

A 3.5-y-old, female rhesus macaque (Macaca mulatta) inoculated with SIVmac239 presented 8 mo later for inappetence and facial bruising. Physical examination revealed a superficial skin abrasion below the left eye, bruising below the left brow, and epistaxis of the left nostril. There were no significant findings on CBC, serum chemistry, urinalysis, or radiographs. Differential diagnoses included infectious etiologies, self-injurious behavior, immune-mediated dermatitis, and neoplasia. Lack of response to antibiotic and analgesic therapy and observations of the macaque made it apparent that the skin lesions were self-inflicted. The excoriations rapidly progressed to extend over the nose, and the left palpebrae became edematous. Euthanasia was elected because the macaque appeared to be experiencing continued discomfort despite analgesic therapy. Histopathologic examination revealed systemic cytomegalovirus (CMV) infection involving the facial nerves, periocular nerves, meninges, and perimesenteric lymph nodes. CMV is a common infection in macaques, with adult seroprevalence close to 100% in most colonies. Infection in immunocompetent animals is usually asymptomatic but can cause significant clinical disease in immunodeficient hosts. CMV is associated with a painful peripheral neuropathy in human AIDS patients, and analgesic treatment is often unsatisfactory. Peripheral neuropathy secondary to CMV should be considered as an underlying cause of self-injurious behavior in SIV-infected macaques. Macaques affected by other diseases and disorders may also be at risk for development of painful peripheral neuropathies.Abbreviations: CMV, cytomegalovirus; HCMV, human CMV; RhCMV, rhesus CMV; SIB, self-injurious behaviorRhesus macaques (Macaca mulatta) are one of the most commonly used NHP species in biomedical research.^9,25 They generally adapt well to captivity, but some develop abnormal behaviors such as stereotypies and self-injurious behavior (SIB).³² Examples of SIB include excessive hair-plucking, head banging, and self-biting that causes wounds in some cases.³² Self-inflicted wounding has been reported in 11% to 14% of individually housed rhesus macaques and can be difficult to manage.^26,32,39 The most commonly discussed risk factors for the development of SIB are related to housing and management, and little is known about potential physiologic causes, such as neuropathic pain.^18,26,32 Compulsive SIB directed toward a specific body part due to neuropathic pain or pruritus occurs in humans.^12,28Rhesus cytomegalovirus (RhCMV) is enzootic in rhesus macaques with close to 100% seroprevalence by 1 y of age in both wild and captive populations.^22,42 As with human cytomegalovirus (HCMV), RhCMV infection is generally subclinical in immunocompetent animals but can cause serious disease in immunodeficient macaques.⁸ RhCMV can be highly pathogenic in SIV-infected animals, and HCMV is the most common viral opportunistic infection in humans with AIDS.^8,37 HCMV infection has been associated with painful peripheral neuropathies in AIDS patients.^17,36,37 We here report a case of SIB associated with RhCMV-induced peripheral neuropathy in an immunocompromised macaque.     

Abdominal Lipomatosis with Secondary Self-Strangulation of Masses in an Adult Rhesus Macaque (Macaca mulatta)

An 10-y-old, intact male rhesus macaque (Macaca mulatta) presented for bilateral scrotal swelling and a distended abdomen. A soft mass in the left upper quadrant of the abdomen was palpated. A barium study did not reveal any gastrointestinal abnormalities. Exploratory laparotomy revealed a large (1.25 kg, 15.0 × 13.0 × 9.5 cm), red and tan, soft, circumscribed, spherical mass within the greater omentum and 10 to 20 smaller (diameter, 1 to 4 cm), soft to firm masses in the mesentery and greater omentum. The resected mass was a self-strangulating abdominal lipoma, a pedunculated neoplasm composed of white adipocytes arising from peritoneal adipose tissue undergoing secondary coagulation necrosis after strangulation of the blood supply due to twisting of the mass around the peduncle. The smaller masses were histologically consistent with simple or self-strangulating pedunculated abdominal lipomas. The macaque presented again 9 mo later with a firm, 5.0-cm mass in the midabdomen, with intestinal displacement visible on radiographs. Given this animal''s medical history and questionable prognosis, euthanasia was elected. Necropsy revealed numerous, multifocal to coalescing, 1.0- to 15.0-cm, pale tan to yellow, circumscribed, soft to firm, spherical to ellipsoid, pedunculated masses that were scattered throughout the mesentery, greater omentum, lesser omentum, and serosal surfaces of the gastrointestinal tract. All of the masses were pedunculated abdominal lipomas, and most demonstrated coagulation necrosis due to self-strangulation of the blood supply. To our knowledge, this report is the first to describe abdominal lipomatosis with secondary self-strangulation of masses in a rhesus macaque.Lipomas have been reported frequently in veterinary medicine as benign subcutaneous neoplasms in canines¹⁶ or as pedunculated peritoneal masses with the potential to cause intestinal strangulation in geriatric horses.⁶ Abdominal lipomatosis (multiple abdominal lipomas) in humans and dogs had been reported only rarely and have been accompanied by clinical signs of abdominal distention with or without secondary gastrointestinal complications.¹⁶ Lipomas of the skin of nonhuman primates have affected a patas monkey, an African green monkey, rhesus macaques, and chimpanzees. Lipomas within the peritoneal cavity have been diagnosed rarely in nonhuman primates. Reported cases include an omental lipoma in a mona monkey and an adrenal lipoma in a hamadryas baboon.¹⁴ Here we report the clinical signs, postmortem examination, and histopathologic features of abdominal lipomatosis in a rhesus macaque (Macaca mulatta).     

Osteochondromatosis in a Rhesus macaque (Macaca mulatta)

A 5-y-old, male, rhesus macaque (Macaca mulatta) presented with a prominent mass slightly anteriomedial to the right stifle. On exam, multiple radiopaque masses were identified protruding from the mid- and distal femur. Lateral and anteroposterior radiographs of the right stifle region revealed multiple exophytic masses arising from the femur, with mild bony reaction of the proximal tibia. Histologic examination of biopsy tissue revealed woven and lamellar bone with granulation tissue and skeletal muscle. Because the macaque was exhibiting no lameness or signs of pain, we decided to monitor the progression of the masses. Minimal change was noted during the time prior to study termination at 6.5 y of age. Necropsy revealed that the bony masses were cartilage-capped lesions arising near the growth plate of the distal femur and midshaft of the femur and tibia. Histologic examination revealed chondro-osseous exophytic growths that blended imperceptibly with the cortex and spongiosa of the femur, consistent with a final diagnosis of multiple osteochondromas.     

Cercopithecine Herpesvirus 9 (Simian Varicella Virus) Infection after Total-Body Irradiation in a Rhesus Macaque (Macaca mulatta)

This case report describes a rhesus macaque (Macaca mulatta; male; age, 5 y; weight, 6.7 kg) with anorexia, dehydration, lethargy, ataxia, and generalized skin rashes that occurred 30 d after total-body irradiation at 6.5 Gy (⁶⁰Co γ-rays). Physical examination revealed pale mucus membranes, a capillary refill time of 4 s, heart rate of 180 bpm. and respirations at 50 breaths per minute. Diffuse multifocal maculopapulovesicular rashes were present on the body, including mucocutaneous junctions. The CBC analysis revealed a Hct of 48%, RBC count of 6.2 × 10⁶/µL, platelet count of 44 × 10³/µL, and WBC count of 25 × 10³/µL of WBC. The macaque was euthanized in light of a grave prognosis. Gross examination revealed white foci on the liver, multifocal generalized petechiation on serosal and mucosal surfaces of the gastrointestinal tract, hemorrhagic lymph nodes, and hemorrhagic fluid in the thoracic cavity. Microscopic examination revealed cutaneous vesicular lesions with intranuclear eosinophilic viral inclusions within the epithelial cells, consistent with herpesvirus. Immunohistochemistry was positive for herpesvirus. The serum sample was negative for antibodies against Macacine herpesvirus 1 and Cercopithecine herpesvirus 9 (simian varicella virus, SVV). Samples submitted for PCR-based identification of the etiologic agent confirmed the presence of SVV DNA. PCR analysis, immunohistochemistry, and histology confirmed that lesions were attributed to an active SVV infection in this macaque. This case illustrates the importance of screening for SVV in rhesus macaques, especially those used in studies that involve immunosuppressive procedures.Abbreviations: SVV, simian varicella virus; TBI, total-body irradiation     

Adenocarcinoma of the Ileocolic Junction and Multifocal Hepatic Sarcomas in an Aged Rhesus Macaque (Macaca mulatta)

An aged male rhesus macaque in our colony had decreased appetite and a loss of interest in behavioral testing. CBC analysis revealed a regenerative, microcytic, hypochromic anemia with thrombocytosis, consistent with iron deficiency. A fecal occult blood test was positive. Ultrasound imaging revealed numerous, vascularized focal liver lesions that suggested metastases. The macaque''s appetite continued to decrease, and he became more lethargic. At this point, the investigator elected to euthanize the macaque. At necropsy, the ileocolic junction was white and abnormally thickened, and the liver was pale tan with approximately 18 discrete white masses randomly scattered throughout the hepatic parenchyma. Histologically, the mass at the ileocolic junction was identified as an intestinal adenocarcinoma, whereas the liver masses were confirmed to be undifferentiated hepatic sarcomas. This case report describes a rhesus macaque that had 2 unrelated primary neoplasms. A review of the literature indicates that this rhesus macaque is the first reported to have an adenocarcinoma of the ileocolic junction and multiple hepatic sarcomas simultaneously.Rhesus macaques (Macaca mulatta) are genetically similar to humans, have a similar aging phenotype at approximately 3 times the rate of those in humans, and develop spontaneous cancers similar to those in humans.³⁶ In humans, gastrointestinal carcinomas are relatively common, but most of these lesions arise in the colon and rectum with only a small percentage in the small intestine and ileum.^4,12,15,18 Although the ileocolic junction is considered a common site for intestinal adenocarcinomas in aged rhesus macaques, this tumor has also been found in the duodenum, jejunum, distal ileum, cecum, and colon.^{6,13,21-23,25,39} Intestinal adenocarcinomas also occur in aged cynomologus macaques (Macaca fasicularis),³⁹ cotton-top marmosets (Saguinus oedipus),^6,10 common marmosets (Callithrix jacchus),^6,27 and a squirrel monkey (Saimiri sciureus).²⁴ Cotton-top marmosets often develop adenocarcinomas of the colon, including the cecum–colon, and rectum.^6,10 Common marmosets have been reported to develop adenocarcinomas of the small intestine.^6,27 Adenocarcinoma of the cecum in a squirrel monkey has been reported.²⁴Spontaneous hepatic tumors unrelated to carcinogenic factors, such as aflatoxin B1,³³ occur only rarely in nonhuman primates. In the United States, primary malignant hepatic tumors in humans are rare, and fewer than 1% are reported to be hepatic sarcomas.^1,16,40 Review of the nonhuman primate literature revealed reports of hepatic cholangiocarcinoma in a 25-y-old male capuchin monkey (Cebus albifrons),⁷ hepatocellular carcinoma in a 24-y-old male squirrel monkey (Saimiri boliviensis)⁵ and in a female squirrel monkey (Saimiri sciureus) older than 13 y,²⁸ and hepatocellular carcinoma and cholangiocarcinoma in an African green monkey (Cercopithecus aethiops).³⁴ Spontaneous hepatocellular carcinomas were reported to occur in 2 adolescent male cynomologus macaques younger than 5 y.³¹ Hepatic hemangiosarcoma was diagnosed in 3-y-old female rhesus macaque,²⁶ and hepatic cholangiocarcinoma was found in a rhesus macaque that also had an intestinal adenocarcinoma.³⁹The aged male rhesus macaque (Macaca mulatta) in the current case study was found to have adenocarcinoma of the ileocolic junction and multiple, random, discrete neoplasms in the liver, which were identified as undifferentiated sarcomas. No metastases from the intestinal adenocarcinoma were detected, but neoplastic cells similar to those of the undifferentiated hepatic cells were identified in an intestinal artery. The frequency of multiple tumor types in aged nonhuman primates is relevant to the use of older animals in research.     

Generalized Seizure Activity in an Adult Rhesus Macaque (Macaca mulatta) during Ketamine Anesthesia and Urodynamic Studies

We report a case of a generalized seizure in an adult female rhesus macaque (Macaca mulatta) undergoing a urodynamic evaluation while she was anesthetized with continuous-infusion ketamine. The seizure presented with generalized tonic–clonic activity during bladder infusion with saline. The tonic–clonic phase was self-limited and was followed by focal facial twitching, which was interrupted by bolus administration of intravenous diazepam. The ictal event was documented as pressure oscillations during cystometrogram recordings and a period of external urethral sphincter muscle activation, which was detectable by electromyography. An acute decrease in urethral pressure was demonstrated at the end of the generalized seizures. Ketamine anesthesia combined with relatively rapid infusion of saline into the bladder may have contributed to the onset of seizures. In addition, this case highlights the value of having a fast-acting benzodiazepine agent available to stop continuous or residual seizure activity during diagnostic or experimental procedures in anesthetized nonhuman primates.Anesthetic agents are used to sedate and immobilize nonhuman primates for veterinary health care and experimental studies. For these purposes, ketamine, a dissociative general anesthetic, is the agent used most commonly in macaques. Several protocols have been developed for the safe administration of ketamine, either as a single agent or as part of a balanced anesthetic approach administered orally, per rectum, intramuscularly, or intravascularly.^9,16,18 Although ketamine and other anesthetic agents are known to suppress physiologic responses during experimental studies, reflexive micturition may still be evoked, as demonstrated by urodynamic recordings in anesthetized rats.^1,2,10 In addition, urodynamic studies have demonstrated that bladder reflexes are suppressed by anesthesia in nonhuman primates, although comparative studies on the effects of different anesthetic agents have suggested that ketamine may be a suitable anesthetic for cystometrograms in rhesus macaques.⁵Here, parenteral administration of ketamine was used to sedate and immobilize adult rhesus macaques for comprehensive urodynamic studies. In one subject, the infusion of saline into the urinary bladder was associated with the acute onset of a generalized seizure, characterized by a self-limited period of tonic–clonic activity, followed by focal facial twitching, which was relieved by prompt intravenous administration of diazepam, and voiding. The tonic–clonic phase of the event was documented by cystometrography and electromyography recordings. We suggest the administration of ketamine anesthesia and the relatively rapid infusion of saline into the bladder as possible factors that may have contributed to the ictal event in this rare case of a clinical seizure during a urodynamic study in a nonhuman primate.     

Use of Femoral Head and Neck Ostectomy and Physical Therapy to Manage Osteoarthritis in a Rhesus Macaque (Macaca mulatta)

Osteoarthritis is associated with pain and immobility in both humans and animals. However, available resources for osteoarthritis management in captive NHP are limited. This case report describes a novel management strategy for a 10-y-old male macaque with unilateral hindlimb lameness, prominent muscle wasting, and severely limited range of motion. Radiographs of the affected limb showed lytic lesions of the femoral head. To relieve pain and improve mobility, femoral head and neck ostectomy (FHO) was performed, and multiple pharmacotherapies were initiated. The macaque also received a unique method of physical therapy that required no sedation, acted as enrichment, and was implemented by using a conventional caging system. The response to therapy was monitored by measuring thigh circumference in the operated and nonoperated limbs, which demonstrated improvement in both legs. The unique physical therapy in conjunction with surgery and pharmacotherapy benefited the macaque with osteoarthritis by reducing discomfort and improving mobility.Abbreviations: FHO, femoral head and neck ostectomy; ROM, range of motionOsteoarthritis is associated with pain and is the leading cause of impaired mobility in aging humans.⁷ Osteoarthritis also is frequently diagnosed in companion animals, and the most common presenting complaint is lameness.⁴ Physical examination findings may include lameness, reduced range of motion (ROM), palpable crepitus, joint instability, and pain during joint manipulation.⁴ In captive NHP, clinical signs may be limited to muscle atrophy,¹² in part because of their natural instincts, as wild animals and as prey species, to hide injury and pain.¹In companion animals, pain from osteoarthritis frequently is managed with a combination of drugs including NSAID, nutritional supplements, and weight reduction.¹¹ If an underlying cause is identified, surgery may be indicated. In addition, physical rehabilitation including ROM exercises, underwater treadmill walking, low-level laser therapy, and acupuncture may be beneficial in managing pain due to osteoarthritis.¹¹Various challenges are associated with managing osteoarthritis in captive NHP. Due to biosafety concerns, physical rehabilitation exercises developed for companion animals are often not feasible. Physical manipulation generally requires chemical sedation; sedation itself may adversely affect hemodynamic and respiratory functions, with an increase in frequency of sedation leading to increased risks.¹³ The chronic use of antiinflammatory medications such as NSAID may be associated with gastrointestinal, hepatic, and renal adverse effects. In addition, published information describing medical and surgical approaches for NHP, especially in regard to postoperative care, is limited.^3,5,12,15This case report involves an adult male rhesus macaque with osteoarthritis that led to unilateral hindlimb lameness and prominent muscle wasting. The macaque was managed with a combination of pharmacotherapy, surgery (femoral head and neck ostectomy [FHO]), and innovative physical therapy.