The authors found that high intrathecal morphine concentrations lead to aseptic intrathecal inflammatory masses. The lack of effect of clonidine and the possible suppressive effects of clonidine on the local reaction suggest the utility of such coadministration.

Objective. To test the hypothesis that nitric oxide (NO) is involved in the pathophysiology of arthritis.Methods. Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. The NO synthase (NOS) inhibitor, NG-monomethyl-Larginine (L-NMA), was administered daily by the oral route for 19 days. Paw swelling, plasma fibrinogen levels, and urinary NOJNO, levels were measured to assess the effect of L-NMA on the arthritic response and whole-body NO production, respectively. On day 20, the ankle joints were processed for histopathologic evaluation.Results. The onset of clinical symptoms was preceded by elevated biosynthesis of NO. In a dosedependent manner, L-NMA inhibited both NO biosynthesis and paw swelling; histopathologic changes in the ankle joints were also prevented. D-NMA had no effect on the development of arthritis, while L-arginine reversed the effects of L-NMA. Fibrinogen levels in rats with arthritis were unaffected by L-NMA.Conclusion. NO is critical to the development of both the inflammatory and erosive components of adjuvant arthritis in rats. There may be a future clinical role for suitable inhibitors of NO production or activity.Rheumatoid arthritis is a chronic, incurable disease characterized by joint swelling, synovial in- flammation, and cartilage destruction. Antagonism of the mediators which drive these pathophysiologic changes represents one approach to improving the treatment of this condition. Such an endeavor requires the prior identification of the appropriate mediators. In a recent review (I), it was suggested that nitric oxide (NO) should be investigated in this regard; the present paper reports the results of a study that was designed to do so.In vitro studies have demonstrated that both the resident mesenchymal cells of the joints and the leukocytes which enter joints during inflammation have the capacity to synthesize considerable amounts of NO. Thus, cultures of articular chondrocytes (2,3) and synoviocytes (4) produce high levels of NO following activation by interleukin-1, a cytokine present in rheumatoid synovial fluids. Macrophages (9, polymorphonuclear leukocytes (6), mast cells (7), and, possibly, lymphocytes (8) are additional potential sources of NO in inflamed joints. Analysis of synovial fluids (9,lO) from arthritic joints has confirmed the presence of elevated amounts of nitrate and nitrite, the stable end products to which NO spontaneously oxidizes in vivo. Previous animal studies have implicated NO in inflammation (1 I), immunity (12), and tissue destruction (13).NO is synthesized by the enzyme NO synthase (NOS), which exists as several isozymes (14), the main distinction being between constitutive (cNOS) and inducible (iNOS) forms. Cells that contain cNOS quickly and transiently produce small amounts of NO in response to agonists which raise intracellular Ca2' concentrations, while cells with iNOS produce large amounts of NO for a prolonged period following a lag of several hours during which the enzyme is induced.Chondrocytes (2),...

Results from epidemiological studies have generally indicated an association of dietary saturated animal fats with human breast cancer risk. Some studies, however, have suggested a similar association for some polyunsaturated vegetable fats shown to promote both rodent mammary carcinogenesis and metastasis. This study was performed to evaluate the effects of corn oil on growth and metastasis of MDA-MB-435 human breast cancer cells, which have a propensity for metastasis. Corn oil is rich in the omega-6 fatty acid linoleic acid. Fifty-eight female athymic nude mice (NCr-nu/nu) were fed a high-fat diet (23% wt/wt corn oil; 12% linoleic acid) or a low-fat diet (5% wt/wt corn oil; 2.7% linoleic acid). Seven days after diets were started, tumor cells (1 x 10(6) were injected into a mammary fat pad. The time to appearance of solid tumors and the tumor size were recorded. After 15 weeks, the study was terminated, and autopsies were performed to determine the weight of the primary tumor and the extent of metastasis. The latent interval for tumor appearance in the animals fed the high-fat diet was shorter than that in the low-fat diet group, and the tumor growth rate in the high-fat diet group showed a small but statistically significant increase compared with the low-fat diet group. Primary tumors developed in 27 of the 29 mice on the high-fat diet and in 21 of the 29 on the low-fat diet. Of the mice with palpable primary tumors, 18 of 27 in the high-fat diet group and eight of 21 in the low-fat diet group had macroscopic lung metastases. The extent of metastasis in the high-fat diet group was independent of the primary tumor weight, but only those in the low-fat diet group with primary tumors weighing more than 2 g developed metastases. These results suggest that a high-fat diet rich in omega-6 polyunsaturated fatty acid can enhance metastasis of human breast cancer cells in this mouse model. The findings support the need for further study of the relationship between dietary polyunsaturated fats and breast cancer risk and for experiments to determine the effect on metastasis of only a 50% difference in fat intake--the dietary goal of the proposed clinical trials of low-fat dietary intervention in breast cancer patients.

-The neuroprotective effects of dexmedetomidine have been reported by many investigators; however its underlying mechanism to reduce neuronal injury during a prolonged anesthesia remains unclear. In this study, we investigated the neurotoxic effects of dexmedetomidine in fetal monkey brains. In the present study, we compare the neurotoxic effects of dexmedetomidine and ketamine, a general anesthetic with a different mechanism of action, in fetal cynomolgus monkeys. Twenty pregnant monkeys at approximate gestation day 120 were divided into 4 groups: non-treatment controls (Group 1); ketamine at 20 mg/kg intramuscularly followed by a 12-hr infusion at 20-50 mg/kg/hr (Group 2); dexmedetomidine at 3 μg/kg intravenously (i.v.) over 10 min followed by a 12-hr infusion at the human equivalent dose (HED) of 3 μg/kg/hr (Group 3); and dexmedetomidine at 30 μg/kg i.v. over 10 min followed by a 12-hr infusion at 30 μg/kg/hr, 10 times HED (Group 4). Blood samples from both dams and fetuses were measured for concentration of dexmedetomidine. Each fetus was perfusion-fixed, serial sections were cut through the frontal cortex, and stained to detect for apoptosis (activated caspase 3 and TUNEL) and neurodegeneration (silver stain). In utero treatment with ketamine resulted in marked apoptosis and degeneration primarily in layers I and II of the frontal cortex. In contrast, fetal brains from animals treated with dexmedetomidine showed none to minimal neuroapoptotic or neurodegenerative lesions at both low-and high-dose treatments. Plasma levels confirmed systemic exposure of dexmedetomidine in both dams and fetuses. In conclusion, these results demonstrate that dexmedetomidine at both low-dose (HED) and highdose (10 times HED) does not induce apoptosis in the frontal cortex (layers I, II, and III) of developing brain of cynomolgus monkeys.

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