Morphine-induced conformational changes in human monocytes, granulocytes, and endothelial cells and in invertebrate immunocytes and microglia are mediated by nitric oxide

We evaluated the contribution of nitric oxide (NO) to morphine-induced rounding of spontaneously activated (mobile) ameboid human monocytes, granulocytes, or arterial endothelial cells and invertebrate immunocytes and microglia. Morphine induced significant rounding and inactivation of ameboid cells within 20 min except for arterial endothelial cells, which became rounded 24 h after morphine exposure. The effects of morphine on cell conformation were blocked in the presence of N-nitro-L-arginine, a nitric oxide synthase inhibitor. Treatment of cells with the NO donor, sodium nitroprusside, induced cell rounding similar to that observed following morphine exposure, suggesting that NO release may mediate morphine-induced changes in cell conformation. The contribution of NO release to morphine-induced cell rounding was determined by direct evaluation of NO concentration in real-time using a NO-specific amperometric probe. Significant increases in NO concentration were observed 2 min after morphine stimulation, whereas morphine-induced NO release was markedly impaired by pretreatment with N-nitro-L-arginine or the opiate alkaloid antagonist, naloxone. In contrast, opioid peptides failed to induce NO release, consistent with our previous observations that demonstrated the failure of opioid peptides to promote cell rounding. Taken together, these data suggest that morphine-induced NO release may be mediated by activation of the opiate alkaloid-selective, opioid peptide-insensitive micro3 receptor, and that functional coupling of morphine to NO production has been conserved during evolution and may modulate cellular activation.     

Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2

OBJECTIVE: To estimate the prevalence and social correlates of cardiovascular disease. DESIGN: Population-based cross-sectional survey. Survey data were obtained through a standardized home interview and a clinic visit by trained nurses. The question sequence of the London School of Hygiene (the Rose Questionnaire) was used to identify the presence of definite angina, possible infarction, definite infarction, intermittent claudication and stroke. SETTING: Eight urban communities and rural areas in Saskatchewan in 1990. PARTICIPANTS: A probability sample of 2167 noninstitutionalized men and women aged 18 to 74 years who participated in the Saskatchewan Heart Health Survey. MAIN OUTCOME MEASURES: Prevalence of cardiovascular diseases. RESULTS: Among men, the prevalence of definite angina increased gradually with age from 1.7% (95% CI 0.6% to 2.7%) in the 18 to 34 year group, 3.8% (1.3% to 6.0%) in the 35 to 54 year group to 4.8% (2.8% to 8.3%) in the 55 to 74 year group, while the prevalence among women ranged from 2.5% (1.2 to 3.7%), 4.0% (1.6% to 6.5%) to 7.1% (5.1% to 11.6%) in these same age groups. The prevalence of possible angina, definite infarction, possible infarction and intermittent claudication increased with age as well, being higher in men than in women. Generally, the conditions were more prevalent among those with less education, lower income and those who were unemployed. CONCLUSIONS: These findings indicate that there is sociodemographic inequality in the prevalence of these manifestations of cardiovascular disease, and there is a need for in-depth qualitative research into causal factors in this relationship and for targeted programs of health promotion.     

Simian virus 40, poliovaccines and human tumors: a review of recent developments

Recently, wild-type SV40 and/or DNA sequences indistinguishable from SV40 have been detected in specific types of human tumors: ependymoma and choroid plexus tumors, mesothelioma, osteosarcoma and sarcoma. The same tumor types will develop in hamsters after injection with SV40. These findings are interesting in themselves for they could shed light on the pathogenesis of these tumors. These findings also have public health implications. SV40 was found to have contaminated the poliovaccines and the adenovaccines from 1955 until 1963, therefore resulting in the inadvertent injection of millions of people with this tumor virus. Moreover, our society pays a high cost for asbestos causality, a carcinogen associated with the development of mesothelioma. In addition to asbestos, the potential impact of finding another possible cause for mesothelioma (i.e., SV40), as well as the possible pathogenic role of the contaminated poliovaccines, has generated considerable public interest and concern. To discuss these recent findings, the NIH (National Institutes of Health) and the FDA (Food and Drug Administration), organized an International Conference at the NIH, Bethesda, MD, January 27-28, 1997. The association of SV40 with human mesothelioma was also discussed in a special session at the IV International Mesothelioma Conference that was held at the University of Pennsylvania, Philadelphia, PA, May 13-16, 1997. The purpose of this review is to summarize data, from the discovery of the contaminated poliovaccines, to the most recent findings presented at the meetings in Bethesda and Philadelphia, to discuss technical and other problems associated with this research, and the potential for using these findings to develop new diagnostic and therapeutic approaches for SV40-associated malignancies.     

Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro

Quinazolinone derivatives I and their methyl esters were synthesized and evaluated as nonclassical lipophilic inhibitors of thymidylate synthase. Compounds Ib and Ic containing OH and CO2H as R substituents, respectively, were most effective, indicating that hydrogen bonding may contribute to the increased inhibitory activity. These compounds further showed high cytotoxic activity against tumor cells in culture.     

A high affinity, mu-opioid receptor-selective enkephalin analogue lacking an N-terminal tyrosine

We report a high affinity, mu opioid receptor selective enkephalin analogue in which the N-terminal tyrosine residue thought to be required for such high affinity is replaced by phenylalanine. The high affinity can be traced to a shift of the ligand's N-terminal residue within the mu receptor binding pocket, which diminishes the importance of the usual hydrogen bond between the tyrosine phenolic moiety and the receptor.     

In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers

OBJECTIVE: To characterize the long-term impact of four hormone therapy regimens on insulin and glucose concentrations measured during a standard oral glucose tolerance test. RESEARCH DESIGN AND METHODS: The Postmenopausal Estrogen/Progestin Intervention Study was a 3-year placebo-controlled randomized trial to assess effects of four hormone regimens on cardiovascular risk factors. This efficacy analysis describes glucose and insulin concentrations from 788 adherent women at baseline and at 1 and 3 years' postrandomization. RESULTS: When compared with women taking placebo, those taking conjugated equine estrogen (CEE) at 0.625 mg/day with or without a progestational agent had mean fasting insulin levels that were 16.1% lower, mean fasting glucose levels 2.2 mg/dl lower, and mean 2-h glucose levels 6.4 mg/dl higher (each nominal P < 0.05). No significant differences were apparent between women taking CEE only versus the three progestin regimens: medroxyprogesterone acetate (MPA) at 2.5 mg daily (continuous MPA), MPA at 10 mg on days 1-12 (cyclical MPA), and micronized progesterone (MP) (cyclical) at 200 mg on days 1-12. The impact of hormone therapy on insulin and glucose depended on baseline levels of fasting insulin and 1-h glucose (P < 0.05). However, the treatment effects on carbohydrate metabolism appeared to be consistent across participant subgroups formed by lifestyle, clinical, and demographic characteristics. CONCLUSIONS: Oral hormone therapy involving 0.625 mg/day of CEE may modestly decrease fasting levels of insulin and glucose. Postchallenge glucose concentrations are increased, however, which may indicate delayed glucose clearance.