17-ß Estradiol reduces atherosclerosis without exacerbating lupus in ovariectomized systemic lupus erythematosus-susceptible LDLr(-/-) mice.

OBJECTIVE: To test the hypothesis that estrogen treatment in a radiation chimera mouse model of systemic lupus erythematosus (SLE) and atherosclerosis will increase SLE-associated atherosclerosis by increasing autoantibody production and inflammation. METHODS: We used a radiation chimera mouse model in which bone marrow from the polygenic B6.Sle1.2.3 model of SLE was transferred to the low density lipoprotein receptor knock out (LDLr(-/-)) model of atherosclerosis on a C57BL/6 background (Sle/LDLr(-/-)). Ovariectomized chimeric mice were treated for 10 weeks with either 5.6 µg/day of 17ß-estradiol or placebo; outcomes included atherosclerosis plaque size, anti-dsDNA autoantibody production and renal pathology. RESULTS: Mean atherosclerosis plaque size was 67.4 ± 7.6% smaller in the estrogen treated group (p < 0.0001). Estrogen treated Sle/LDLr(-/-) mice had no significant difference in serum cholesterol concentration, lipoprotein distribution, anti-dsDNA autoantibody concentration, antibody isotype concentration and renal histopathology score compared to placebo. However, they had significantly lower mean urine protein to urine creatinine ratio (UP:UC). There was no correlation between atherosclerosis lesion size and either the renal histology score or UP:UC ratio in Sle/LDLr(-/-) mice. CONCLUSION: These results indicate that 17ß-estradiol is atheroprotective within the context of murine SLE independent of changes in serum cholesterol concentration, autoantibody concentration, or renal pathology. The SLE phenotype in Sle/LDLr(-/-) mice is not exacerbated by exogenous 17ß-estradiol administration, and the reduced UP:UC ratio suggests a protective effect against lupus nephritis.

Comparative pathology of smallpox and monkeypox in man and macaques.

In the three decades since the eradication of smallpox and cessation of routine vaccination, the collective memory of the devastating epidemics caused by this orthopoxvirus has waned, and the human population has become increasingly susceptible to a disease that remains high on the list of possible bioterrorism agents. Research using surrogate orthopoxviruses in their natural hosts, as well as limited variola virus research in animal models, continues worldwide; however, interpretation of findings is often limited by our relative lack of knowledge about the naturally occurring disease. For modern comparative pathologists, many of whom have no first-hand knowledge of naturally occurring smallpox, this work provides a contemporary review of this historical disease, as well as discussion of how it compares with human monkeypox and the corresponding diseases in macaques.

Clinicopathologic characterization of naturally occurring diabetes mellitus in vervet monkeys.

Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasting hyperglycemia, and it can be of either polygenic or monogenic origin. Animal models have played an important role in elucidating the pathophysiology of the polygenic Type 1 and type 2 DM forms; however, useful animal models of the monogenic forms do not exist. The authors describe 4 cases of naturally occurring DM in vervet monkeys (Chlorocebus aethiops sabaeus), 1 of which has clinicopathologic findings consistent with type 2 DM, including persistent hyperglycemia, hypertriglyceridemia, islet amyloidosis, and reduced islet insulin immunostaining. In contrast, the 3 remaining animals have clinicopathologic similarities to a monogenic form of the disease, including a lack of islet amyloidosis and hypertriglyceridemia, as well as normal islet insulin immunostaining. In addition, pedigree analysis conducted on one of these animals is consistent with either an autosomal dominant or mitochondrial inheritance pattern, which supports a monogenic form of DM. The authors thus hypothesize that a naturally occurring monogenic form of diabetes may occur in vervet monkeys, making them a potential animal model for future studies.

Histologic and immunohistochemical characterization of spontaneous pituitary adenomas in fourteen cynomolgus macaques (Macaca fascicularis).

Pituitary adenomas were identified in 14 of 491 (2.9%) cynomolgus macaques evaluated from 1994 to 2004. Cases included male (8) and female (6) cynomolgus macaques ranging from 18 to 32 years of age. Seven of the pituitary adenomas caused gross enlargement of the pituitary gland that was visible on postmortem examination, whereas the remaining 7 were multifocal microadenomas identified on histologic examination. A total of 35 adenomas were identified in the 14 macaques, 6 of which were being treated for diabetes mellitus. Mean (+/- SD) pituitary weight was 0.31 +/- 0.42 g, compared with 0.07 +/- 0.02 g for 430 historical control animals (P < 0.0001). Immunohistochemical staining for follicle-stimulating hormone, luteinizing hormone, prolactin, human growth hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone was applied to pituitary tissue from all cases. Immunostaining revealed 22 of 35 (62.9%) lactotroph adenomas, 5 of 35 (14.3%) plurihormonal cell adenomas, 3 of 35 (8.6%) corticotroph adenomas, 2 of 35 (5.7%) null cell adenomas, 1 of 35 (2.9%) somatotroph adenomas, 1 of 35 (2.9%) mixed corticotroph-somatotroph adenomas, 1 of 35 (2.9%) mixed lactotroph-corticotroph adenomas, 0 of 35 gonadotroph adenomas, and 0 of 35 thyrotroph adenomas. This study represents the first extensive retrospective case series performed to evaluate the histologic and immunohistochemical characteristics of pituitary adenomas in cynomolgus macaques. Our findings indicated that macaque pituitary adenomas frequently had mixed histologic appearance and hormone expression, and that, similar to human pituitary adenomas, prolactin-secreting neoplasms were the most prevalent type.