CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function.

Chemokine receptors are implicated in inflammation and immune responses. Neuro-inflammation is associated with activation of astrocyte and amyloid-beta (Aß) generations that lead to pathogenesis of Alzheimer disease (AD). Previous our study showed that deficiency of CC chemokine receptor 5 (CCR5) results in activation of astrocytes and Aß deposit, and thus memory dysfunction through increase of CC chemokine receptor 2 (CCR2) expression. CCR5 knockout mice were used as an animal model with memory dysfunction. For the purpose LPS was injected i.p. daily (0.25 mg/kg/day). The memory dysfunctions were much higher in LPS-injected CCR5 knockout mice compared to CCR5 wild type mice as well as non-injected CCR5 knockout mice. Associated with severe memory dysfuction in LPS injected CCR5 knockout mice, LPS injection significant increase expression of inflammatory proteins, astrocyte activation, expressions of ß-secretase as well as Aß deposition in the brain of CCR5 knockout mice as compared with that of CCR5 wild type mice. In CCR5 knockout mice, CCR2 expressions were high and co-localized with GFAP which was significantly elevated by LPS. Expression of monocyte chemoattractant protein-1 (MCP-1) which ligands of CCR2 also increased by LPS injection, and increment of MCP-1 expression is much higher in CCR5 knockout mice. BV-2 cells treated with CCR5 antagonist, D-ala-peptide T-amide (DAPTA) and cultured astrocytes isolated from CCR5 knockout mice treated with LPS (1 µg/ml) and CCR2 antagonist, decreased the NF-ĸB activation and Aß level. These findings suggest that the deficiency of CCR5 enhances response of LPS, which accelerates to neuro-inflammation and memory impairment.

Peroxisome proliferator di-isodecyl phthalate has no carcinogenic potential in Fischer 344 rats.

Di-isodecyl phthalate (DIDP), a peroxisome proliferator-activated receptor-alpha activator, is widely used as a plasticizer in the manufacture of polyvinyl chloride (PVC), and ultimately in typical vinyl applications, particularly wire, cable and toys, etc. To examine its carcinogenic potential, DIDP was fed to Fischer 344 rats in the diet at doses of 0, 400, 2000 and 8000 ppm for 2 years. Briefly, significant decreases in the overall survival and body weights, and increases in the relative weights of kidneys and liver were noted in both sexes of the highest dose groups. However, no treatment-related neoplastic lesions were observed in the internal organs, including the liver. Unlike di(2-ethylhexyl) phthalate (DEHP), DIDP failed to maintain the catalase-inducing potential between early and late expressions of catalase protein from western blotting, immunohistochemistry and enzyme activity measurements. These results suggest that the non-carcinogenicity of DIDP in F344 rats was due to its limited potential for peroxisomal proliferating activity.

Disseminated transmissible venereal tumor in a dog.

Transmissible venereal tumor (TVT) is a well-documented transplantable tumor in dogs, with no breed or sex predilection and a low metastatic rate. In this report, a 2-year-old intact female Mastiff that had numerous, rapidly growing masses throughout the subcutis mainly at the dorsal body plane, the caudal half of the ventral abdomen, and around the vulva was euthanized due to poor prognosis. Neoplastic nodules similar to those seen in the subcutis were also noted in the lung, anterior mediastinum, liver, spleen, kidney, and superficial and deep lymph nodes in both abdominal and thoracic cavities. The neoplastic nodules from the subcutis as well as metastatic foci revealed similar cytologic and histologic features, which were consistent with canine TVT. By immunohistochemical staining, the neoplastic cells were positive for lysozyme and vimentin but were negative for cytokeratin, desmin, CD3, and CD79a. The diagnosis of the TVT was further supported by the identification and analysis of long interspersed nuclear elements (LINE) from paraffin-embedded tumor tissue. This case is a rare example of TVT with multiorgan metastasis. In this case, the polymerase chain reaction technique was useful in differential diagnosis of canine round cell tumors because this technique can be applied in retrospective as well as future study.

Intra-abdominal mass aspirate from a cat in heat.

A 3-year-old intact female domestic shorthair cat was presented for the evaluation of a palpable intra-abdominal mass in the left caudal abdomen. The cat had a history of anorexia, depression and prolonged estrus over a period of about 1 month. Smears prepared from a fine needle aspirate of the mass revealed large round to oval cells arranged individually or in loose clusters surrounded by pink, fibrillar matrix material. Cytoplasm was basophilic, with many variably-sized vacuoles and variable numbers of small purple granules. The vacuoles within the cells were strongly positive with Oil-Red-O stain. The cytologic features were most suggestive of a neoplasm of epithelial cell origin or inadvertent aspiration of a fatty liver. At laparotomy, the mass was found to involve the left ovary. Histologically, the tumor consisted of dense sheets and nests of irregular polyhedral, pleomorphic cells with abundant, finely vesiculated cytoplasm. The tumor cells were separated into lobules by strands of connective tissue. Based on histologic evaluation, a diagnosis of ovarian luteoma was made. In this report, we document the cytologic and histologic features of an uncommon feline tumor, a luteoma, and address its possible misdiagnosis as hepatic lipidosis when using cytology alone to make a diagnosis.

The selective cyclooxygenase-2 inhibitor nimesulide prevents Helicobacter pylori-associated gastric cancer development in a mouse model.

PURPOSE: Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is overexpressed in the stomach during H. pylori infection. Therefore, we investigated whether nonsteroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide on H. pylori-associated gastric carcinogenesis in mice. EXPERIMENTAL DESIGN: C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, nimesulide was mixed with feed pellets and administered for the duration of the experiment. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide. RESULTS: Gastric tumors developed in 68.8% of mice that were given both MNU and H. pylori, whereas less than 10% developed gastric tumors when given either MNU or H. pylori alone. These findings indicate that H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, nimesulide administration substantially reduced H. pylori-associated gastric tumorigenesis, whereas substantial inductions of apoptosis were observed. In vitro studies demonstrated that nimesulide and H. pylori when combined acted synergistically to induce more apoptosis than either alone. CONCLUSIONS: Our data show that nimesulide prevents H. pylori-associated gastric carcinogenesis, and suggest that COX-2 may be a target for chemoprevention of gastric cancer.