Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus.

This study's objective was to assess the effects of PD-0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony-stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD-0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre- and post-treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14(+) CD16(+) monocytes, urinary N-terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater-than-dose-proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14(+) CD16(+) cells, uNTX, ALT, AST and CK levels at most time-points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between-group differences were seen in CLASI. Patients receiving PD-0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD-0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end-points.

Polioencephalomalacia secondary to hypernatremia in squirrel monkeys (Saimiri sciureus).

Squirrel monkeys (Saimiri spp) are one of the most consistently used New World primates in biomedical research and are increasingly being used in neuroscience research, including models of drug abuse and addiction. Spontaneous neurologic disease in the squirrel monkey is uncommonly reported but includes various infectious diseases as well as cerebral amyloidosis. Hypernatremia is an extremely serious condition of hyperosmolarity that occurs as a result of water loss, adipsia, or excess sodium intake. Neurologic effects of hypernatremia reflect the cellular dehydration produced by the shift of water from the intracellular fluid space into the hypertonic extracellular fluid space. Severe hypernatremia may result in cerebrocortical laminar necrosis (polioencephalomalacia) in human patients as well as in a number of domestic species, including pigs, poultry, and ruminants. We report the clinical, histopathologic, and immunohistochemical findings of polioencephalomalacia in 13 squirrel monkeys. Polioencephalomalacia in these animals was associated with hypernatremia that was confirmed by serum levels of sodium greater than 180 mmol/L (reference range, 134.0-154.0 mmol/L [mEq/L]). All animals had concurrent diseases or experimental manipulation that predisposed to adipsia. Immunohistochemical investigation using antibodies to neuronal nuclei (NeuN), CNPase, Iba-1, and CD31 revealed necrosis of predominantly cerebral cortical layers 3, 4, and 5 characterized by neuronal degeneration and loss, oligodendrocytic loss, microglial proliferation, and vascular reactivity. The squirrel monkey is exquisitely sensitive to hyperosmolar metabolic disruption and it is associated with laminar cortical necrosis.

Epizootic myocarditis associated with encephalomyocarditis virus in a group of rhesus macaques (Macaca mulatta).

Six cases of fatal myocarditis associated with encephalomyocarditis virus occurred over a 14-month period in a group of outdoor-housed juvenile rhesus macaques. All animals were younger than 3 years of age and died or were euthanized following acute onset of dyspnea or pulmonary effusion (3 of 6) or were found dead without premonitory signs (3 of 6). Gross findings included pulmonary congestion (6 of 6), variable degrees of pleural effusion (4 of 6), multifocal pale tan foci throughout the myocardium (3 of 6), hepatomegaly and hepatic congestion (3 of 6), and pericardial effusion (1 of 6). Histologically, affected myocardium was infiltrated multifocally by lymphoplasmacytic and histiocytic inflammation admixed with necrotic and degenerate myofibers and infrequent mineralization (6 of 6). Pulmonary edema was present in all animals. Encephalomyocarditis virus was confirmed in 6 of 6 hearts by immunohistochemistry, and virus was isolated from one case by polymerase chain reaction. Sequencing of virus isolated from 1 affected animal indicated infection with a novel encephalomyocarditis virus. Encephalomyocarditis virus should be considered as a differential etiology in outbreaks of myocarditis and pulmonary edema in juvenile primates.

Histologic and immunohistochemical characterization of pheochromocytoma in 6 cotton-top tamarins (Saguinus oedipus).

Pheochromocytomas are uncommon neoplasms of the adrenal medulla that are most frequently reported in rats and select mouse strains. In many cases, especially those in man, pheochromocytoma is associated with familial tumor syndromes, because of inherited mutations in a variety of proto-oncogenes and tumor suppressor genes. Nonhuman primates are valuable animal models for a variety of human diseases because of their similar anatomy and physiology; however, cases of pheochromocytomas have only rarely been reported in nonhuman primates. Herein, we characterize the gross, histologic, and immunohistochemical features of pheochromocytoma in 6 cotton-top tamarins (Saguinus oedipus). Pheochromocytomas represented 6 of 114 of the total causes of death in the studied population (5.3%) and corresponded to 16% of the total number of neoplasms. The average age of affected animals was 17.9 years. On histologic examination, all cases were defined by tight bundles, nests, and cords of neoplastic chromaffin cells. All cases had concurrent myocardial degeneration and fibrosis of varying severity and chronicity. Three of the cases (50%) also had hyalinization and medial thickening of coronary arteries consistent with hypertension. On immunohistochemical examination, 6 of 6 of the cases (100%) stained positively for chromogranin A, synaptophysin, N-CAM (or CD56), and protein gene product 9.5. None of the cases stained for glial fibrillary acidic protein. Pedigree analysis revealed inter-relatedness in 4 of 6 animals, with progenitor animals also affected with pheochromocytomas. The tumors in this population illustrate comparable histologic and immunohistochemical staining patterns with cases in other laboratory animals and humans, and, therefore, may indicate common underlying genetic alterations that precipitate tumor development.