Food intake and body temperature responses of rats to recombinant human interleukin-1 beta and a tripeptide interleukin-1 beta antagonist.

Food intake and body temperature are two of many factors affected by IL-1 beta, a cytokine which is produced in response to tissue injury and inflammatory processes. In the present experiment, a tripeptide IL-1 beta antagonist which blocked IL-1 beta-induced hyperalgesia was tested for the ability to block IL-1 beta-induced effects on food intake and body temperature. Food intake was decreased 4-22 h after intraperitoneal (IP) administration of 1.25, 1.88, or 2.50 micrograms IL-1 beta/rat, and 0-22 h food intake was decreased by 1.88 and 2.50 micrograms IL-1 beta/rat. The effect of 1.25 micrograms IL-1 beta/rat on food intake measured 4 and 22 h after (IP) injection was blocked by coadministration of 5 mg tripeptide IL-1 beta antagonist. However, 25 mg tripeptide IL-1 beta antagonist/rat plus 1.25 micrograms IL-1 beta/rat decreased 0-22 h food intake more than IL-1 beta alone. Administration (IP) of 1.25 micrograms IL-1 beta/rat increased body temperature 1 degrees C 4 h later, and 5 and 25 mg tripeptide IL-1 beta antagonist/rat blocked this increase. Although food intake remained decreased after IL-1 beta administration alone or with 25 mg tripeptide IL-1 beta antagonist/rat for 22 h, body temperature returned to normal under these conditions. Thus, a tripeptide IL-1 beta antagonist shown to block IL-1 beta-induced hyperalgesia also blocked food intake and body temperature responses to IL-1 beta, although the effective doses of IL-1 beta and the tripeptide IL-1 beta antagonist differ by 4,000-fold when both are administered peripherally.     

Model adducts of benzo[a]pyrene and nucleosides formed from its radical cation and diol epoxide.

Reference adducts formed by reaction of deoxyribonucleosides with the ultimate carcinogenic forms of benzo[a]pyrene (BP), BP radical cation and BP diol epoxide, are essential for identifying the structures of adducts formed in biological systems. Electrochemical oxidation of BP in the presence of dG or dA produces adducts from BP radical cation. When 8 equiv of charge are consumed, four adducts are formed with dG: 7-(BP-6-yl)Gua, 8-(BP-6-yl)Gua, N2-(BP-6-yl)dG and 3-(BP-6-yl)dG. With 2 equiv of charge, however, only 7-(BP-6-yl)Gua and 8-(BP-6-yl)dG (BP-6-C8dG) are formed. Anodic oxidation of BP-6-C8dG affords 8-(BP-6-yl)Gua. Anodic oxidation of BP in the presence of dA produces 7-(BP-6-yl)Ade. Reaction of BP diol epoxide with dG yields 10-(guanin-7-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydroBP, whereas reaction with dA affords three adducts, 10-(adenin-7-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydroBP and two isomers of 10-(deoxyadenosin-N6-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydroBP . On the basis of comparative kinetic studies among adducts of aromatic hydrocarbons and dG or G, only BP-6-C8dG easily loses the sugar moiety, providing a basis for a mechanism of hydrolysis of the glycosidic bond.     

Comparative dose-response tumorigenicity studies of dibenzo[alpha,l]pyrene versus 7,12-dimethylbenz[alpha]anthracene, benzo[alpha]pyrene and two dibenzo[alpha,l]pyrene dihydrodiols in mouse skin and rat mammary gland

Comparative studies were conducted of the tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a,l]pyrene (DB[a,l]P) versus 7,12-dimethyl-benz[a]anthracene (DMBA), the most potent recognized carcinogenic polycyclic aromatic hydrocarbon (PAH); benzo[a]pyrene (B[a]P), the most potent recognized carcinogenic environmental PAH; DB[a,l]P 8,9-dihydrodiol, the K-region dihydrodiol; and DB[a,l]P 11,12-dihydrodiol, precursor to the bay-region diolepoxide. The tumor-initiating activity of DB[a,l]P and B[a]P was compared in the skin of female SENCAR mice at doses of 300, 100 and 33.3 nmol. The mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice-weekly for 13 weeks. DB[a,l]P at all doses induced significantly more tumors than B[a]P at the corresponding dose, with a significantly shorter latency. Subsequently, the tumor-initiating activity of DB[a,l]P was compared in the skin of female SENCAR mice to that of DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol and DB[a,l]P 11,12-dihydrodiol at doses of 100, 20 and 4 nmol. The mice were promoted with TPA twice-weekly for 24 weeks. In addition, groups of mice were initiated with 100 nmol of DB[a,l]P, DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol or DB[a,l]P 11,12-dihydrodiol and kept without promotion. This experiment showed that in the mouse skin, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol displayed similar tumor-initiating activity with a response inversely proportional to the dose, presumably due to the toxicity of the compounds. At the high dose they elicited tumors earlier than DMBA, though DMBA produced a much higher tumor multiplicity. At the low dose, DMBA, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol exhibited similar tumorigenicities. DB[a,l]P 8,9-dihydrodiol was a marginal tumor initiator. Once again, DB[a,l]P was by far a much stronger tumor initiator than B[a]P. Female Sprague-Dawley rats were treated with 1.0 or 0.25 mumol of DB[a,l]P, DMBA or B[a]P by intramammillary injection at eight teats. DB[a,l]P at both doses was a more potent carcinogen than DMBA at the corresponding dose in the rat mammary gland. B[a]P was a marginal mammary carcinogen, eliciting only a few fibrosarcomas. Thus, these data suggest that DB[a,l]P is the strongest PAH carcinogen ever tested.     

Syncarcinogenic effect of the environmental pollutants cyclopenteno[cd]pyrene and benzo[a]pyrene in mouse skin

Benzo[a]pyrene (BP) and cyclopenteno[cd]pyrene (CPEP) are widespreadenvironmental pollutants. CPEP is a relatively potent carcinogenin mouse skin with an activity second only to BP among environmentalaromatic hydrocarbons. We have studied the combined applicationof BP and CPEP on mouse skin to determine their possible synergisticcarcinogenic effect. Nine-week-old female Swiss mice in groupsof 30 were treated on the back with high (H), medium (M) andlow (L) doses, respectively, of 20 (H), 6.6 (M) or 2.2 (L) nmolBP or 200 (H), 66.6 (M) or 22.2 (L) nmol CPEP in 50 µlacetone twice weekly for 48 weeks. Other groups received BP-H+ CPEP-H, BP-M + CPEP-M, BP-L + CPEP-L, BP-H + CPEP-L, BP-M+ CPEP-L, BP-L + CPEP-H, or BP-L + CPEP-M. A significant, 3-to 7-fold syncarcinogenic effect occurred when BP-M + CPEP-Mwere administered together. A smaller, but significant, synergisticeffect (1.2- to 3.8-fold) was also observed when BP-M + CPEP-Lor BP-L + CPEP-M was applied. Because of the syncarcinogeniceffect of BP and CPEP, their abundance in engine emissions andambient air samples may present a major source of carcinogenicrisk.     

Minimal-exposure transfusion and the committed donor

Autologous blood (collected preoperatively or salvaged intraoperatively) is the safest blood available for transfusion, but its use is not always feasible. It may be possible to decrease a patient's exposure to homologous donors. Pediatric cardiac surgery patients frequently are unable to donate autologous blood preoperatively. Since 1984, attempts have been made to provide parental apheresis platelets and intraoperative blood salvage to such patients to decrease their donor exposure. Further decreases in donor exposure have been the object of a program of collecting from one committed donor all the blood a patient is anticipated to need. This article reviews the experience with 50 pediatric cardiac surgery patients on such a program, in whom the mean decrease in homologous-donor exposure was 57 percent (range, 12-93%). Thirteen of these patients received only homologous blood products from one committed donor, for a mean decrease in homologous-donor exposure of 80 percent (range, 50-93%). A comparison of 12 of these 13 recipients with a matched control group showed no significant difference in red cell transfusion practice but a significant difference in the number of homologous-donor exposures per m2 of body surface area (BSA) (mean donor exposures/m2 of BSA: patients = 1.5, controls = 10.5). The use of one committed donor and autologous blood can provide a minimal-exposure transfusion.