Retrospective analysis of an outbreak of B virus infection in a colony of DeBrazza's monkeys (Cercopithecus neglectus).

In 1981, an outbreak of herpetic disease developed in a colony of DeBrazza's monkeys (Cercopithecus neglectus). In seven of eight infected animals, clinical signs of infection included vesicular and ulcerative lesions on the lips, tongue, and/or palate. Histologic examination of lesions revealed intranuclear inclusion bodies, and electron microscopy revealed nucleocapsids and virions with typical herpesvirus morphology. Although a virus was isolated that appeared similar to monkey B virus, techniques available at the time did not allow precise identification of the virus. Analysis of serum from one surviving monkey collected 12 years after the outbreak revealed a pattern of reactivity characteristic of B virus-positive serum on the basis of results of ELISA and western immunoblot analysis. Polymerase chain reaction analysis of archived paraffin-embedded tissue specimens and molecular analysis of the one viral isolate obtained from a DeBrazza's monkey indicated that the virus responsible for the outbreak was a new genotype of B virus. Testing of sera from lion-tailed macaques (Macaca silenus) housed in an adjacent cage at the same zoo indicated that these animals harbored this virus and, thus, were the likely source of the virus that infected the DeBrazza's monkeys. This study documents usefulness of archiving samples from disease outbreaks for later analysis. In addition, this incident underscores the importance of considering herpes B virus infection when outbreaks of disease having characteristics of herpetic infections develop in nonhuman primates kept at institutions that also house macaques.

Salmonellosis in laboratory-housed iguanid lizards (Sceloporus spp.).

Fifteen wild-caught iguanid lizards (14 Sceloporus variabilis and one S. malachiticus) were used in a 3 mo study on thermal acclimation. Over a 2 mo period, five of the lizards showed decreased activity, anorexia and enlarged joints, and were either found moribund or were euthanatized due to their poor condition. Specimens taken from lesions in four of the five lizards were cultured and were infected with Salmonella spp. Salmonella spp. was cultured from cloacal swabs in six of the 10 surviving lizards. Standard metabolic rates of those that were infected did not differ significantly from those that were not infected. We postulate that the lizards were inapparent carriers of Salmonella spp. at the time of capture and, as a result of stress, five developed active overwhelming systemic infections.

Amyloidosis in pigtailed macaques (Macaca nemestrina): epidemiologic aspects.

A retrospective study of amyloidosis in pigtailed macaques (Macaca nemestrina) at the Washington Regional Primate Research Center (WRPRC) was conducted. Between 1971 and 1985, 248 of 1,952 (13%) necropsies revealed amyloidosis in pigtailed macaques. The influence of demographic factors, diseases and experimental interventions on amyloidosis was examined. Univariate analyses, using two controls for each case, indicated that age, sex, birthplace and residence were related to amyloidosis. After adjusting for age, females were not at greater risk. However, monkeys born at the WRPRC were at greater risk and monkeys 0 to 5 years old residing at the breeding colony were at greater risk than monkeys at the research center. After adjustment for age, monkeys were at greater risk of developing amyloidosis if they had a history of episodes of diarrhea, respiratory disease or trauma. As the number of episodes increased, the risk increased. Monkeys with retroperitoneal fibromatosis, a manifestation of simian D retrovirus infection, were also at greater risk. Using logistic regression and controlling for age, sex, birthplace and residence, monkeys with diarrhea remained at an elevated risk for amyloidosis. Compared with a model combining diarrhea, respiratory disease, septicemia, surgery, trauma and retroperitoneal fibromatosis, a model with diarrhea alone accounted for most of the increased risk.

Amyloidosis in pigtailed macaques (Macaca nemestrina): pathologic aspects.

The pathologic aspects of 248 cases of amyloidosis in pigtailed macaques (Macaca nemestrina) at the Washington Regional Primate Research Center from 1971 through 1985 were studied. Amyloid was present in the spleen, liver and gastrointestinal (GI) tract, either alone or in combination, in nearly 75% of the monkeys. Its occurrence declined with age in the spleen and the GI tract, but increased with age in the liver. Both intestinal inflammation and retroperitoneal fibromatosis were strongly associated with amyloid deposition in the GI tract. Monkeys with histopathologic findings of enteritis or enterocolitis and glomerulonephritis were at increased risk of developing amyloidosis. Forty cases of amyloidosis with a history of chronic diarrhea had type AA amyloid by histochemical tests.

Atrophic rhinitis in New Zealand white rabbits infected with Pasteurella multocida.

Atrophic rhinitis was detected in New Zealand White rabbits when upper respiratory tract disease was evaluated during a vaccine field trial for the prevention of pasteurellosis. Of 52 adult rabbits euthanatized and necropsied, 26 (50%) had evidence of turbinate atrophy. Atrophy was detected in 77% of rabbits with Pasteurella multocida infection only, 71% of rabbits with concurrent P multocida and Bordetella bronchiseptica infections, and 6% of rabbits with B bronchiseptica infection only. Grossly, turbinate atrophy was characterized by a mild to severe loss or diminution in the maxilloturbinates. Histologically, turbinate bones were small and irregular in thickness and had numerous osteoclasts and osteoblasts. A neutrophilic exudate filled the nasal passages, and infiltrates of neutrophils and lymphocytes were detected in the mucosa and submucosa of the nasal turbinates. Rhinitis was significantly (P less than 0.001) associated with turbinate atrophy. Isolates of P multocida from rabbits with turbinate atrophy were serotype A:12.

Neoplasms in NIH type II athymic (nude) mice.

Necropsy and histopathology were performed over an 18-month period on 173 NIH type II athymic (nude) mice and 53 NIH type II mice heterozygous at the nu locus. A total of 149 mice were used in studies of tumor transplantation while 77 mice were screened as part of the quality assurance program for the colony. Twenty-nine neoplasms were found in 173 nu/nu mice. Only one neoplasm, an ovarian granulosa cell tumor, was found in 53 nu/+ mice. In nu/nu mice, there were nineteen lymphosarcomas, nine ovarian granulosa cell tumors, and one transitional cell carcinoma of the urinary bladder. A greater number of lymphosarcomas occurred in mice greater than 6 months old. A greater number of tumors, particularly lymphosarcomas, were found in nu/nu mice than in nu/+ mice.

Life table analysis and pathologic observations in male mice of a long-lived hybrid strain (Af X C57BL/6)F1.

We have utilized a long-lived (Af X C57BL/6)F1 hybrid strain of mice for a variety of aging studies. In this report we have characterized the life expectancy and pattern of spontaneous deaths in 202 mice, malignant and nonmalignant lesions in 64 male mice dying spontaneously, and organ weights and lesions in 39 male mice killed at selected ages. The maximum age observed was 41.5 months. The principal causes of death were malignant lymphoma and alveologenic neoplasms, which were present in 56.3% and 45.3%, respectively, of the mice dying spontaneously. A variety of other neoplastic and non-neoplastic lesions that are not infrequently seen in older mice were observed in these mice. Neoplasms seen in these mice that are rare in other mice included disseminated mast cell tumors in two mice and gastric adenocarcinoma in one mouse. In comparing the diseases observed in this hybrid strain with those reported for the parent strains, there was an incidence of malignant lymphoma similar to the C57BL/6 parent, an incidence of alveologenic neoplasms intermediate between the parent strains, and a markedly reduced incidence of amyloidosis. This study provides a detailed background of baseline hematologic and morphologic data in a long-lived hybrid of two commonly used strains of mice.

Spontaneous hypertension and its sequelae in woolly monkeys (Lagothrix lagotricha).

Arteriolar nephrosclerosis was observed at necropsy in 26 of 38 woolly monkeys (Lagothrix lagotricha). This lesion is the earliest histologic change associated with hypertension in humans. Seventeen of the monkeys had died of congestive heart failure, renal failure or acute cardiovascular accident, complications similar to those seen in human hypertension. All monkeys known to be over 4 years of age were affected. Direct blood pressure measurements in nine otherwise healthy woolly monkeys revealed systolic pressures of 194 +/- 20 mmHg. Our physiologic, clinical and pathologic studies suggest that woolly monkeys develop hypertension spontaneously and could be a useful model for the study of human hypertension.

Dichlorvos toxicity in the white-footed mouse (Peromyscus leucopus).

The organophosphate pesticide, dichlorvos (DDVP), is used commonly to control ectoparasites in laboratory rodents colonies. This compound is relatively nontoxic to Mus musculus at dosages several times the therapeutic level. However, usage of a similar therapeutic level in the white-footed mouse (Peromyscus leucopus) resulted in substantial mortality. To determine whether P. leucopus is more susceptible than M. musculus to the toxic effects of DDVP, both species were exposed to 0, 3 and 6 g of pelleted DDVP per cage. In a subsequent experiment, P. leucopus were exposed to 0 and 1 g of DDVP per cage. Mortality was not observed in M. musculus at any dosage level. P. leucopus exposed to 1, 3 and 6 g of DDVP exhibited mortalities of 3%, 20% and 53%, respectively. Mean serum cholinesterase in P. leucopus exposed to 3 and 6 g of DDVP was 0.35 and 0.21 U/ml as compared to 3.13 U/ml in unexposed mice. The analogous values for M. musculus were 1.60 and 0.79 U/ml while the level in unexposed mice was 6.79 U/ml. In the second experiment, mean serum cholinesterase in P. leucopus exposed to 1 g of DDVP was 0.32 U/ml as compared to 2.33 U/ml in unexposed mice. Histopathology revealed no lesions in the brain, liver or kidneys. The increased susceptibility of P. leucopus to the toxic effects of DDVP was related to the lowered serum cholinesterase. This indicates that DDVP should not be used for control of ectoparasites in P. leucopus.

Experimental Sendai virus infection in laboratory rats. I. Virus replication and immune response.

Sixty 5 to 8 week old Sprague-Dawley (Crl:CD(SD)BR) rats were inoculated intranasally with 2000 egg infectious doses of egg-propagated Sendai virus. Virus was recovered from the upper respiratory tract and lungs on days 1 through 8 post-inoculation (PI). Serum antibody responses were measured for 12 rats over a 9 month period PI. Antibody was first detected at 7 days, peaked at 21 days, and was detected in 5 of the 12 rats at 9 months. A cell-mediated response, as measured by lymphocyte blastogenesis, also was detected at 7 days and peaked at 21 days, but was not detected at 6 months PI. Lung and serum interferon (IFN) was first detected at 3 hours and peaked at 6 hours, but was not detected by 160 hours. Lung IFN levels were 4 to 10 times those in the serum. These studies indicate that pathogenesis of Sendai virus infection in the rat is similar to that reported in the mouse, but that there are differences in the kinetics of both viral replication and morphologic changes, as described in the companion paper.

Experimental Sendai virus infection in laboratory rats. II. Pathology and immunohistochemistry.

Intranasal inoculation of 5 to 8 week old specific pathogen-free Sprague-Dawley rats with 5 X 10(3) egg infectious doses of Sendai virus resulted in severe rhinitis, bronchiolitis and alveolitis. The most severe rhinitis occurred on postinoculation (PI) days 4-6, and pneumonia on day 4. Rhinitis and pneumonia persisted to PI day 21, with peribronchial lymphoid infiltration detectable at PI day 42. Immunohistochemical studies showed that Sendai virus antigens were present primarily in columnar epithelial cells of the respiratory mucosa of the nasal cavity and in bronchiolar and alveolar epithelium. Antigen was first detectable at PI day 1, was most prominent at days 3-4 and was undetectable after day 7. More antigen could be seen in the nasal mucosa than in the lung at any stage in the infection. These studies show that Sendai virus by itself is capable of evoking severe, although transient, rhinitis and pneumonia in laboratory rats free of other significant pathogens.

Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice.

These studies were performed to assess the chronic toxicity and oncogenicity of ethylene glycol (EG) in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-1 mice per sex were fed diets yielding approximate dosages of 1.0, 0.2, or 0.04 g/kg/day of EG. Two separate control groups in each study received no EG. Mortality rate was increased in high-dose male rats all of which died by 475 days. The following effects were also observed in high dose male rats: reduced body weight gain, increased water intake, increased blood urea nitrogen and creatinine, reduced erythrocyte count, reduced hematocrit and hemoglobin, increased neutrophil count, increased urine volume, reduced specific gravity and pH. Urinary calcium oxalate crystals and increased kidney weight were seen in all high-dose rats. Uric acid crystals were seen in the urine of high-dose female rats at 18 and 24 months. Histopathologic changes in high-dose male rats included tubular cell hyperplasia, tubular dilation, peritubular nephritis, parathyroid hyperplasia, and generalized soft tissue mineralization. Fatty change of the liver was seen in high- and intermediate-dose female rats. No clinical signs, or gross or microscopic evidence of toxicity was seen in mice at the dosages used. Water intake and clinical pathologic parameters were not measured in the mouse study. In these studies there was no evidence of an oncogenic effect of EG in rodents.

Nasal cavity neoplasia in F344/N rats and (C57BL/6 x C3H)F1 mice inhaling propylene oxide for up to two years.

Propylene oxide (CAS: 75-56-9) was studied for potential carcinogenicity and chronic toxicity by inhalation in F344/N rats and (C57BL/6 x C3H)F1 mice. Groups of 50 animals of each sex were exposed to 0, 200, or 400 ppm propylene oxide for 6 hours/day, 5 days/week, for up to 103 weeks. Survival decreased in mice exposed to propylene oxide; the decrease was significant (P less than .005) in mice exposed to 400 ppm. Survival of exposed rats was comparable to that of controls. Mean body weight of rats and mice exposed to 400 ppm propylene oxide decreased, when compared to that of controls, during the 2d year of exposure. Exposure to propylene oxide for up to 2 years induced inflammatory and proliferative responses in nasal cavity of both species. There was clear evidence of carcinogenicity in mice exposed to 400 ppm propylene oxide; 10 of 50 males and 5 of 50 females had hemangiomas or hemangiosarcomas of the nasal submucosa. Papillary adenomas involving the nasal respiratory epithelium and underlying submucosal glands were observed in 3 female rats and 2 male rats exposed to 400 ppm propylene oxide.

Retroperitoneal fibromatosis and acquired immunodeficiency syndrome in macaques: clinical and immunologic studies.

A simian acquired immunodeficiency syndrome (SAIDS) associated with retroperitoneal fibromatosis (RF) has been observed in several species of macaque at the Washington Regional Primate Research Center. Clinical signs were recurrent diarrhea, weight loss, mesenteric lymphadenopathy, and opportunistic infections. Most affected macaques in the later stages of illness showed marked immunodeficiency. Response of peripheral blood mononuclear cells to mitogens was impaired significantly. There was sharply depressed primary and secondary antibody response to the T-cell dependent antigen, bacteriophage phi X174. Affected monkeys did not switch from IgM to IgG antibody following a secondary immunization, as did normal macaques. Twenty-four (67%) of 36 affected animals with progressive RF or deteriorated stages of illness had hypoproteinemia and hypoalbuminemia. Quantitative serum immunoglobulins of 23 cases showed that eight (35%) had hypogammaglobulinemia, six (26%) had hypergammaglobulinemia, and the remainder (39%) were within the normal range. Opportunistic infections were predominantly bacterial pathogens. Type D retrovirus appeared to be closely associated with RF-affected macaques (12/12 or 100%). The case fatality rate (including animals sacrificed after prolonged illness) was 98%. The leading cause of death was due directly to RF lesions in 43%, to enterocolitis in 36%, septicemia in 12%, amyloidosis in 5%, and malignant lymphoma (2%). Clinical, immunologic and pathologic changes reveal an acquired immunodeficiency syndrome that has many similarities to human AIDS. SAIDS and RF may be a useful model for studying human AIDS.

Verminous vasculitis, pneumonia and pulmonary infarction in a cynomolgus monkey after treatment with ivermectin.

An apparently healthy cynomolgus monkey (Macaca fascicularis) died 2 hours after routine inhalation anesthesia and implantation of a femoral catheter. Gross necropsy findings included patchy raised areas of severe pulmonary hemorrhage and consolidation. Filarioid nematodes (Edesonfilaria malayensis) were located in pulmonary blood vessels and in numerous 0.1-2 cm fibrous cysts on the pleural surfaces of the lungs, pericardium, diaphragm, retroperitoneum, and in the urinary bladder wall. Microscopic lesions included verminous vasculitis, pulmonary infarcts and pneumonia. Many of the nematodes were more necrotic than the surrounding host tissue. During quarantine, 17 days before surgery, the monkey had been given a single dose of ivermectin (200 micrograms/Kg, intramuscular) as an anthelminthic for gastrointestinal nematodes. It is postulated that many of the filarioid nematodes were killed by this treatment. These parasitic emboli caused pulmonary infarction and the severe inflammatory reaction. The resulting pulmonary disease compromised pulmonary function and contributed to death after anesthesia. This complication should be considered if monkeys possibly harboring filarioid nematodes are treated with ivermectin.

Retroperitoneal fibromatosis and acquired immunodeficiency syndrome in macaques: epidemiologic studies.

At the University of Washington Regional Primate Research Center, a simian acquired immunodeficiency syndrome (SAIDS) associated with retroperitoneal fibromatosis (RF) has been observed in 82 macaques since 1976, including 77 pigtailed macaques (Macaca nemestrina), two long-tailed macaques (M. fascicularis), one Japanese macaque (M. fuscata) and two rhesus macaques (M. mulatta). The syndrome is characterized by immunodeficiency accompanied by a fibroproliferative lesion, primarily affects young monkeys (1-3 years) and has a high case fatality rate. Based on the occurrence of RF in colony-born and non-colony-born monkeys, the minimum incubation period for natural exposure is believed to be about 9 months. The incidence of RF was 0.9% in M. nemestrina, 0.1% in M. fascicularis, 1.0% in M. fuscata and 0.4% in M. mulatta. There were no significant differences in the incidence of RF by sex or seasonality. Epidemiologic studies were focused on 42 juvenile M. nemestrina that developed RF between January 1980 and June 1983, and the results were compared with 42 age- and sex-matched controls. The incidence of RF was 5.7% in monkeys 12-24 months old and 3.4% in monkeys 24-36 months old, but less than 1.0% in age groups of under 1 year and over 3 years. No significant associations were found for housing history, parentage, generations or ancestral origins. Epidemiologic information and preliminary viral studies suggest a type D retrovirus may be the causative agent in RF and SAIDS. RF associated with SAIDS appears to be an excellent model for Kaposi's sarcoma associated with human AIDS.

Subacute nonsuppurative hepatitis associated with hepatitis B virus infection in two cynomolgus monkeys.

Subacute, nonsuppurative hepatitis was diagnosed in a cynomolgus monkey (Macaca fascicularis) based on histopathologic examination of a liver biopsy specimen. Clinical signs of illness included anorexia, lethargy and hepatomegaly. Abnormal laboratory findings included elevations of serum liver enzymes, bilirubin and a monocytosis. Circulating antibody (anti-HBs) against Hepatitis B surface antigen (HBsAg) was present in serum and antigens reactive with anti-HBsAg antiserum were found in the liver using an immunoperoxidase technique. Of the remaining 18 healthy monkeys in the same room, another cynomolgus monkey was HBsAg seropositive. Both of the seropositive monkeys involved arrived on the same shipment from Indonesia and had been quarantined and housed together continuously during the preceding two years.

Subcutaneous fibromatosis associated with an acquired immune deficiency syndrome in pig-tailed macaques.

A spontaneous multifocal subcutaneous fibromatosis is described in 6 pig-tailed macaques (Macaca nemestrina) with simian acquired immune deficiency syndrome (simian AIDS). The lesions consisted of a proliferation of vascular fibrous tissue that was infiltrated by lymphocytes and plasma cells. One animal also had retroperitoneal fibromatosis, which has also been found in this colony of pig-tailed macaques. Progressive weight loss, diarrhea, lymphadenopathy, and neutropenia were seen. Peripheral lymph nodes were hyperplastic, and there was splenomegaly. Aggregates of lymphocytes were present in the bone marrow, kidneys, liver, and lungs. Type D retrovirus particles were found in three nodules by electron microscopy; intracytoplasmic type A and budding particles were identified in fibroblasts. In a setting of acquired immunodeficiency, these subcutaneous tumors in pig-tailed macaques present a striking analogy to Kaposi's sarcoma in human AIDS.