Termination Of Sustained Tachycardia By External Noninvasive Pacing

Invasive cardiac pacing has proved useful in the induction and termination of reentrant sustained tachycardias. In one of our two cases, programmed ventricular extra-stimulation was used to induce sustained ventricular tachycardia from the endocardial surface of the right ventricle. Induced ventricular tachycardia was terminated by burst ventricular pacing with an external cardiac pacemaker. In our second patient, external pacing was effective at inducing and terminating sustained supraventricular tachycardia. These patients illustrate that the principles of terminating sustained reentrant tachycardia with invasive pacing may also apply to noninvasive external pacing. The usefulness of this approach in treating reentrant tachycardias needs further evaluation.     

Absence of Developmental Effects in CF-1 Mice Exposed to Aspartame in Utero

Aspartame (L-aspartyl-L-phenylalanine methyl ester) is a widelyused high potency dipeptide sweetener. Developmental toxicologystudies have been performed in several species documenting noeffects of high doses of aspartame. Recently, a study by Mahalikand Gautieri ((1984) Res Commun. Psychol Psychiatry Behav. 9,385–403) reported a delay in the achievement age for thevisual placing response in mice pups after maternal administrationof high dosages of aspartame during late gestation. In the presentstudy developmental parameters were determined in offspringof CF-1 mice after maternal administration of aspartame at 500,1000, 2000, and 4000 mg/kg body wt by oral gavage. Aspartamewas administered on Days 15 through 18 of gestation. Maternalbody weight, food consumption, gestation length, reproductiveindices, and litter size were not affected by aspartame treatment.In the pups, body weights, negative geotaxis, and surface andmidair righting reflexes were not altered by treatment. Therewas no delay in the development of the visual placing responseregardless of the method employed for assessment (grid or rope)or the manner by which the data were analyzed. There were alsono changes in time of eye opening, reflex pupil closure, andophthalmoscopic examination in the offspring. Thus, neitherphysical nor functional development was altered in mice afterin utero exposure to extremely large dosages of aspartame. Morespecifically, in utero exposure to aspartame did not affectthe development of the visual system in mice.     

Immunosuppressive and Monooxygenase Induction Activities of Highly Chlorinated Diphenyl Ether Congeners in C57BL/6 and DBA/2 Mice

The dose-response effects of 2,2',3,3',4,5,5',6,6'–,2,2',3,3',4,4',5,6,6'-and2,2',3,3',4,4',5,5',6-nonachlorodiphenyl ether (non-aCDE) anddecachlorodiphenyl ether (decaCDE) on the splenic plaque-formingcell (PFC) response to sheep red blood cells (SRBCs) and theinduction of hepatic microsomal ethoxyresorufin O-deethylase(EROD) activity was determined in aryl hydrocarbon (Ah)-responsiveC57BL/6 and less Ah-responsive DBA/2 mice. All the congenersexhibited immunotoxicity at doses between 2.5 and 10 µmol/kgin C57BL/6 mice whereas in DBA/2 mice doses25 µmol/kgwere required to cause inhibition of the PFC response to SRBCs.The results also showed that the nonaCDE isomers and decaCDEwere more active as inducers of hepatic EROD activity in C57BL/6than DBA/2 mice; however, there was not a correlation betweenthe induced EROD activity and the CYP1A1 and CYP1A2 mRNA levelsin the C57BL/6 mice. These data suggested that the immunotoxicityof these compounds was mediated through the Ah receptor. However,the results showed that the immunotoxicity of the nonaCDE isomersand decaCDE was unexpectedly high compared to that of lowerchlorinated diphenyl ethers and there were no apparent structure-activityrelationships among the higher chlorinated congeners. This suggeststhat some of the immunosuppressive effects observed for thenonaCDE isomers and decaCDE may be Ah receptor-independent.     

Dose-Dependent Carcinogenicity and Frequent Ki-ras Proto-oncogene Activation by Dietary N-Nitrosodiethylamine in Rainbow Trout

While the experimental data upon which current concepts in mechanisticallybased risk assessment and molecular epidemiology are groundedderive almost entirely from rodent models, fish models haveseveral attributes (e.g., low background incidence, extremelylow cost tumor studies, nonmammalian comparative status forextrapolation of mechanisms to humans) that make them valuableadjuncts for addressing these concepts. This report providesan initial characterization of the dose dependency of dietaryN-nitrosodiethylamine (DEN) hepatocarcinogenicity in Shastastrain rainbow trout (Oncorhynchus mykiss) and the potentialof DEN to elicit ras proto-oncogene activation in this species.Carcinogen was administered in the diet at five concentrationsfor 12 months. Necropsies were per formed at 9, 12, and 18 months,the latter on fish maintained on control diet for 6 months aftercessation of DEN exposure. The incidence of hepatic neoplasmsat the lower dietary concentrations (70 ppm) did not consistentlyexceed that for control groups, which were higher in this particularstudy (2%) than expected (historically 0.1%). For the higherDEN concentrations, a linear relationship between the hepatictumor incidence (expressed as log odds, log [p/(1-p)1, wherep = proportion of fish bearing tumors), and the logarithm oftotal cumulative dose was observed, with response being independentof the length of time (9 or 12 months) during which the dosewas accumulated. The dose-response curve for fish maintainedan additional 6 months postexposure was shifted toward higherincidence but was parallel to the curve for fish killed at cessationof exposure. The model predicts that doubling the dose willproduce some what more than a doubling of the odds (pl(100 -p) for tumor incidence and that the odds for lesions 6 monthspostexposure will be approximately double those at cessationof exposure. Comparison of these results with previous studiesusing rats suggests an overall similarity in dose-response curves,with trout being somewhat less sensitive than rats to DEN hepatocarcinogenesis. To examine the molecular basis for DEN carcinogenesis in this species, seven liver tumors induced separatelyby short-term DEN treatment were probed by 3'-mismatch primerpolymerase chain reaction analysis for evidence of Ki-ras proto-oncogeneactivating point mutations. A very high proportion (6/7) oftumors was found to carry codon 12 GGA - AGA mutations, whereasno codon 61 mutants were detected in this sample. These initialresults differ from those reported using hepatic tumors fromDEN-treated mice, which exhibit frequent Ha-ras codon 61 mutations[Richardson et al., Carcinogenesis 13, 1277–1279 (1992)]and rats, which appear not to carry DEN-activated ras alleles[Bauer-Hoffman et al., Carcinogenesis 11, 1875–1877 (1990)].Thus the available oncogene data for the common carcinogen DENdo not suggest a simple, consistent oncogenic pathway or mutationalspectrum useful in the molecular epidemiology of human cancers.     

Reproductive Toxicity of Sulfamethazine in Swiss CD-1 Mice during Continuous Breeding

Sulfamethazine (SMZ) was evaluated for reproductive toxicityin Swiss CD-1 mice using a continuous breeding protocol. SMZwas administered in the diet at 0, 0.25, 0.5, or 1% (w/w), whichrepresented an average daily intake of 0, 313, 625, or 1250mg SMZ/kg/day, respectively. Exposure of F0 male and femalemice to 1% SMZ for 126 days resulted in a significant decreasein the mean number of live pups per litter and the number oflitters produced (task 2); the percentage pups born alive to1% SMZ females showed a nonsignificant decrease versus controlfemales. The effects on fertility were rapid to onset (1 to4 weeks) and cumulative in nature. F0 male and female body weightswere slightly depressed from 3 weeks to the end of the study.The crossover mating trial (task 3) revealed that the adverseeffect on ferility involved both treated partners in that littersize decreased when either 1% SMZ males were bred to controlfemales or 1% SMZ females were mated with control males. Afterapproximately 155 days of exposure of F0 mice to 1% SMZ, theterminal body weight of 1% SMZ females was significantly decreasedand that of 1% SMZ males showed a nonsignificant decrease. Inaddition, the liver weight to body weight ratio of the maleswas increased. Further, the prostate and seminal vesicle weightto body weight ratios were decreased in 1% SMZ males relativeto control males. No treatment-related gross or histopathologicallesions were noted for the pituitary or reproductive organsof either sex. Sperm assessment indicated no significant differencein the epididymal sperm concentration or percentage motile orabnormal sperm. In conclusion, SMZ was found to be a reproductivetoxicant in the male and female Swiss CD-1 mouse, albeit atrelatively high dietary intake (1250 mg/kg/day), and in thepresence of mild systemic toxicity.     

CHOLECYSTOKININ (PANCREOZYMIN)

The acetyl-derivative of the biologically active C-terminal 7-peptide portion of cholecystokinin (CCK), N-acetyl-O-sulfate-L-tyrosyl-L-methionyl-glycyl-L-tryptophyl-L-methionyl-L-aspanyl-L-phenylalanine amide was prepared by the condensation of 2-peptide segments with 1-isobutyloxycarbonyl-2-isobutyloxy-1,2-dihydroquinoline as coupling reagent. The N-terminal residue, tyrosine, was incorporated by the active ester method. The same 7-peptide was prepared also by stepwise chain-lengthening, starting with the C-terminal residue. The 9-fluorenylmethyloxycarbonyl group was applied for the protection of α-amino functions. In the release of amylase from acinar cells of the pancreas of guinea pigs, the acetyl-7-peptide amide was about 3 times more potent than CCK 27–33 and equal in potency to CCK 26–33. The new derivative strongly stimulated the contraction of the in situ guinea pig gall bladder.     

Five-Month Oral (Diet) Toxicity/lnfectivity Study of Bacillus thuringiensis Insecticides in Sheep

Five-Month Oral (Diet) Toxicity/Infectivity Study of Bacillusthuringiensis Insecticides in Sheep. HADLEY, W. M., BURCHIEL,S. W., MCDOWELL, T. D., THILSTED, J. P., HIBBS, C. M., WHORTON,J. A., DAY, P. W., FRIEDMAN, M. B., and STOLL, R. E. (1987).Fundam. Appl. Toxicol. 8, 236–242. Bacillus thuringiensisinsecticides (Bt) [Dipel (test substance D or Thuri-cide-HP(test substance T)] were administered in the diet for 5 monthsto castrated mixed ram-bouillet/merino sheep (24–34 kgat the beginning of the study) at a dose of 500 mg/kg/day (approximately10¹² spores per day). No treatment-related effect was seen onweight gain or clinical chemistry parameters nor were significantgross clinical changes observed. Several blood and tissue samplestaken just prior to the time the animals were killed or at necropsywere found to be positive for Bt when cultured. Detailed grossand microscopic pathologic examination of the sheep revealedseveral incidental lesions. However, the only lesion that mayhave been associated with the treatment was lymphocytic hyperplasiain Peyer's patches seen in the cecum of three sheep and it wasnot considered to be clinically significant.