Pancreatic endocrine tumour with disseminated pulmonary thromboembolism in an owl monkey (Aotus nancymae).

Pulmonary thromboembolism associated with pancreatic endocrine neoplasia is extremely uncommon in man and animals. Post-mortem examination of an adult owl monkey (Aotus nancymae) revealed extensive pulmonary arterial thromboembolism and a well-demarcated mass attached to the pancreas. Microscopically, the mass consisted of areas of interstitial fibrosis with loss of acini and islets and replacement by nests and sheets of polygonal cells with amphophilic cytoplasm, an eccentric round nucleus with stippled chromatin and, in some cells, with a single prominent eccentric nucleolus. Clusters of these cells were noted within vessels and adjacent lymph nodes. The cells did not express S100 or insulin, but were labelled strongly with SP-1/chromogranin. Rare individual cells expressed glucagon and somatostatin. A few cells in pulmonary thrombi/emboli and the adjacent lymph node also expressed SP-1/chromogranin. Based on cell morphology, location and immunohistochemistry the tumour was classified as pancreatic endocrine (islet cell) carcinoma with metastasis to regional lymph nodes and lung.

Amelanotic melanoma in a New Zealand White Rabbit (Oryctolagus cuniculus).

A 3.5-year-old intact male double-transgenic New Zealand white rabbit (Oryctolagus cuniculus), apoA-I and LCAT (apolipoprotein and lecithin:cholesterol acyltransferase), was presented with a discrete, raised facial mass (0.5 x 1.0 x 1.0 cm). The mass was surgically excised, with reoccurrence to the same site 88 days later. A second surgical excision was performed, and the rabbit died 3 weeks later from respiratory distress. At necropsy, multiple varying-sized masses were observed in the ventral mandibular region and throughout the lungs, pleura, and diaphragm. On histopathology, the masses were composed of moderately anisocytotic and anisokaryotic polygonal to spindloid cells with moderate finely granular, lightly eosinophilic cytoplasm, having round to oval nuclei with one to several nucleoli and finely stippled chromatin. Mitotic figures were frequent. Lymphatic and venous invasion were noted with neoplastic cells metastasized to the submandibular lymph nodes, lungs, liver, and adventitial surface of the aorta. Fontana-Masson stain was negative for melanin, thereby necessitating immunohistochemistry and transmission electron microscopy. Positive staining with MART-1 (a melanocyte protein marker) combined with transmission electron microscopy revealing type II melanosomes confirmed the diagnosis of an amelanotic melanoma.

A rhabdomyoma within a multilocular thymic cyst in a p53-null mouse.

A 9-month-old p53-null female mouse was found dead in its cage. At necropsy, a large thymic mass encompassed the heart. Microscopically, the mass was composed of numerous varying-sized cysts lined with simple squamous epithelial cells to columnar ciliated cells. Also present within this mass was a large aggregate of loosely arranged fusiform-shaped cells. These cells also were found in smaller numbers in the connective tissue surrounding the cysts. The larger aggregate of fusiform cells was positive for desmin and S-100 and negative for smooth muscle actin. Electron microscopy revealed well-formed Z lines and I bands of skeletal muscle phenotype. A diagnosis of rhabdomyoma within a congenital multilocular thymic cyst was made. The thymus contains a small population of myoid cells, which should be taken in consideration when evaluating thymic tumors.

Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia.

Patients with glycogen storage disease type Ia (GSD-Ia) develop renal disease of unknown etiology despite intensive dietary therapies. This renal disease shares many clinical and pathological similarities to diabetic nephropathy. We studied the expression of angiotensinogen, angiotensin type 1 receptor, transforming growth factor-beta1, and connective tissue growth factor in mice with GSD-Ia and found them to be elevated compared to controls. While increased renal expression of angiotensinogen was evident in 2-week-old mice with GSD-Ia, the renal expression of transforming growth factor-beta and connective tissue growth factor did not increase for another week; consistent with upregulation of these factors by angiotensin II. The expression of fibronectin and collagens I, III, and IV was also elevated in the kidneys of mice with GSD-Ia, compared to controls. Renal fibrosis was characterized by a marked increase in the synthesis and deposition of extracellular matrix proteins in the renal cortex and histological abnormalities including tubular basement membrane thickening, tubular atrophy, tubular dilation, and multifocal interstitial fibrosis. Our results suggest that activation of the angiotensin system has an important role in the pathophysiology of renal disease in patients with GSD-Ia.

Solitary biliary hamartoma with cholelithiasis in a domestic rabbit (Oryctolagus cuniculus).

Hamartomas of the liver and biliary system are extremely rare entities in both animals and humans. Biliary hamartomas in humans are usually multiple and constitute the von Meyenburg complexes. This report describes the presence of a large solitary mass arising from the edge of the right medial liver lobe of a domestic rabbit. Histologically, the mass was composed of an extensive network of large varying sized cystic structures lined by simple cuboidal to columnar epithelium within an abundant fibrous stroma. Within many of the cyst lumina were varying sized, pale white to greenish hard concretions identified as choleliths and were analyzed and found to be composed of calcium carbonate. This is the first known report of biliary hamartoma with cholelithiasis in rabbits.

Eosinophilic crystalline pneumonia as a major cause of death in 129S4/SvJae mice.

Eosinophilic crystalline pneumonia is an idiopathic disease that occurs in many strains and stocks of mice, more commonly in strains on a C57BL/6 background. The disease occurs sporadically in most strains of mice and varies from mild and subclinical to severe and fulminating, sometimes resulting in respiratory distress and death. In this study, 94 aged male and female 129S4/SvJae mice were evaluated for eosinophilic crystalline pneumonia lesions. There was an 87% incidence, with females overrepresented. Histologically, there were multifocal to coalescing inflammatory infiltrates composed of numerous large eosinophilic macrophages and multinucleate cells admixed with eosinophils, neutrophils, lymphocytes, and plasma cells within alveolar and bronchiolar spaces, associated with refractile, brightly eosinophilic, angular crystals. Alveolar macrophages and multinucleate cells contained fine needlelike to rectangular intracytoplasmic crystalline material. Similar crystals were often free within alveoli and conducting airways, often associated with mucous metaplasia of bronchiolar epithelium. This disease may occur spontaneously or in concert with other pulmonary lesions, such as pulmonary adenomas, lymphoproliferative disease, allergic pulmonary disease, and parasitic or fungal infections. The characteristic crystals morphologically resemble Charcot-Leyden crystals, which represent eosinophil breakdown products in humans with eosinophil-related disease. However, crystals in eosinophilic crystalline pneumonia are composed predominantly of Ym1 protein, a chitinase-like protein associated with neutrophil granule products and secreted by activated macrophages. The function of Ym1 protein is not fully understood but is believed to be involved in host immune defense, eosinophil recruitment, and cell-cell and cell-matrix interactions consistent with tissue repair. The mechanism of induction of eosinophilic crystalline pneumonia with Ym1 crystal formation is unknown.

Hyperplastic and neoplastic lesions of the mammary gland in macaques.

Macaques provide an important animal model for the study of hormonal agents and their effects on risk biomarkers for breast cancer. A common criticism of this model is that spontaneous breast cancer has rarely been described in these animals. In this report, we characterize 35 mammary gland lesions ranging from ductal hyperplasia to carcinoma in situ and invasive ductal carcinoma in cynomolgus and rhesus macaques. Based on a retrospective analysis, we estimated the lifetime incidence of mammary gland neoplasia in aged female macaques to be about 6%. Hyperplastic lesions (n = 19) occurred segmentally along ducts and included such features as columnar alteration, micropapillary atypia, and fibroadenomatous change. In situ carcinomas (n = 8) included solid, comedo, cribriform, and micropapillary elements, encompassing 4 of the major architectural patterns seen in human lesions. Invasive ductal carcinomas (n = 8) were generally solid, with prominent central necrosis and mineralization, often on a background of micropapillary ductal hyperplasia and in situ carcinoma. Cytologic changes of invasive lesions included increased mitoses, nuclear pleomorphism, extensive microinvasion, and stromal desmoplasia. Axillary lymph-node metastases were confirmed in 5 of the 8 invasive carcinomas. On immunohistochemistry, intraductal and invasive carcinomas had increased Ki67/MIB1 and HER2 expression and selective loss of estrogen and progesterone receptors. These findings suggest that breast cancer is an underreported lesion in macaques and highlight unique morphologic and molecular similarities in breast cancer between human and macaque species.

Conversion of the severe to the moderate disease phenotype with donor leukocyte microchimerism in canine leukocyte adhesion deficiency.

Leukocyte adhesion deficiency-1 (LAD-1), a genetic immunodeficiency disease characterized by life-threatening bacterial infections, results from the defective adherence and migration of leukocytes due to mutations in the leukocyte integrin CD18 molecule. Canine LAD (CLAD) represents the canine homologue of the severe phenotype of LAD-1 in children. In previous studies we demonstrated that non-myeloablative stem cell transplantation from matched littermates resulted in mixed donor-host chimerism and reversal of the disease phenotype in CLAD. In this study, we describe two CLAD dogs with less than 2% donor leukocyte chimerism following non-myeloablative transplant. Both dogs are alive more than 24 months after transplant with an attenuated CLAD phenotype resembling the moderate deficiency phenotype of LAD. The improvement in the CLAD phenotype with very low levels of donor CD18(+) leukocytes correlated with the preferential egress of the CD18(+) neutrophils into extravascular sites. The clinical response with very low levels of donor CD18(+) leukocytes in CLAD supports using this model for testing gene therapy strategies since the low levels of gene-corrected hematopoietic cells expected with hematopoietic gene therapy would likely have a therapeutic effect in CLAD.

Extramedullary hematopoiesis in the mandibular lymph node of simian-human immunodeficiency virus-infected rhesus monkeys (Macaca mulatta): a report of three cases.

Three cases of extramedullary hematopoiesis (EMH) in the mandibular lymph nodes of rhesus monkeys, experimentally infected intravenously with a chimeric simian human immunodeficiency virus, are described. On histopathologic evaluation, multiple sections of mandibular lymph node from all animals showed evidence of EMH, which included erythroid, myeloid, or megakaryocytic precursor cells (or all) within the medullary sinuses. Immunohistochemistry was used for positive identification of multiple cell types. Evidence of EMH was not observed in numerous sections of axillary, inguinal, cervical, hilar, or mesenteric lymph nodes or in any other tissues examined. To our knowledge, this is the first report on EMH within the lymph nodes of rhesus monkeys without an obvious underlying disease process or stringent blood-sampling schedule warranting the need for increased hematopoiesis outside the confines of the bone marrow.

A variant of pulmonary alveolar microlithiasis in nackt mice.

Four adult mutant nackt mice, which demonstrate alopecia and CD4+ T-cell deficiency, and two outbred SENCAR mice (sentinels) were presented for routine health surveillance. Lesions were not observed at necropsy. Microscopically, all four nackt mice demonstrated multiple concretions that were 30-100 microm in diameter, irregularly rounded to oval, nonbirefringent, and amphophilic to basophilic. Many of the concretions appeared attached to or within the alveolar walls of all lung lobes. Approximately half of the concretions had irregular fracture lines. All concretions were periodic acid-Schiff positive, and Von Kassa staining revealed diffuse calcification. None of the concretions were associated with inflammatory cell infiltrates, and metaplastic ossification was not evident. A diagnosis of pulmonary alveolar microlithiasis, a rare disease in both humans and animals, was made based on the size and location of the concretions and the lack of an inflammatory response. This is the first report of a laboratory mouse demonstrating pulmonary alveolar microlithiasis.

Haemophilus somnus isolated from a urachal abscess in a calf.

A urachal abscess was diagnosed in a 2-month-old, crossbred heifer that was presented for a distended abdomen and clinical signs of choking. Cultures of the mucopurulent exudate, obtained from within the mass on necropsy, yielded Haemophilus somnus. This is the first known documented report of H. somnus isolated from a urachal abscess.

Scapular fractures in dogs: epidemiology, classification, and concurrent injuries in 105 cases (1988-1994).

A retrospective study of canine scapular fractures diagnosed and treated from 1988 through 1994 at four veterinary teaching hospitals was performed. Dogs (n = 105) with 109 scapular fractures were included. Most scapular fractures occurred in young (i.e., less than four years of age), male, medium- to large-breed (i.e., greater than 10 kg) dogs as the result of vehicular trauma. Concurrent injuries (primarily thoracic trauma) occurred in approximately 70% of cases. In-house follow-up evaluations were considered adequate in only 17% of the cases. A classification system that includes biomechanical principles for categorization is described to avoid discrepancies between various traditional classification systems.

Bioavailability of lead to juvenile swine dosed with soil from the Smuggler Mountain NPL Site of Aspen, Colorado.

Bioavailability of lead (Pb) has become an issue in quantifying exposure of sensitive populations and, where necessary, establishing cleanup levels for contaminated soil. Immature swine were used as a model for young children to estimate the degree to which Pb from two fully characterized composite samples from the Smuggler Mountain Superfund Site in Aspen, Colorado may be bioavailable to resident children. The composite soils contained 14,200 and 3870 micrograms Pb/g of soil. Relative and absolute enteric bioavailabilities of Pb in soil (oral dose groups of 75,225, and 675 micrograms Pb/kg body wt/day) were estimated by comparison with an orally administered soluble Pb salt (lead acetate = PbAc2.3H2O) (dose groups of 0, 75, and 225 micrograms Pb/kg body wt/day) and an intravenously administered aqueous solution of Pb (100 micrograms Pb/kg/ day) from the same trihydrate salt administered daily for 15 days to 50 juvenile swine. The biological responses (area under the blood Pb concentration-time curve, and the terminal liver-, kidney-, and bone-lead concentrations) produced by Pb from PbAc2.3H2O and lead-contaminated soils were determined. This study revealed Pb from soil containing 14,200 micrograms Pb/g of soil had a bioavailability relative to Pb from PbAc (RBA), ranging from 56% based on the area under the blood lead concentration-time curve (AUC) versus dose, to 86% based on calculations from liver-Pb loading versus dose. Similarly, Pb from soil containing 3870 micrograms Pb/g of soil had an RBA ranging from 58% based on the AUC versus dose, to 74% based on calculations from liver- and kidney-Pb loading versus dose. Bioavailability of Pb in soils may be more or less than EPA's default RBA of 60%, therefore, measuring site-specific RBAs provides a basis for improved exposure and risk assessment.