Potency of a Complex Mixture of Polychlorinated Dibenzo-p-dioxin, Dibenzofuran, and Biphenyl Congeners Compared to 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Causing Fish Early Life Stage Mortality

Use of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity equivalentsconcentration (TEC) assumes that polychlorinated di benzo-p-dioxins(PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs) act additivelyand via a common mechanism to cause toxicity. To test theseassumptions, 11 TCDD-like congeners and three non-TCDD-likecongeners were combined at ratios typically found in Lake Michiganlake trout. The potency of the mixture, expressed as TEC basedon fish-specific toxic equivalency factors, was compared toTCDD for producing lake trout and rainbow trout early life stagemortality. Signs of toxicity following exposure of newly fertilizedeggs to the mixture or to TCDD were indistinguishable; sac frymortality associated with blue-sac disease, and slopes of thedose-response curves for percentage sac fry mortality versusegg TEC or versus egg TCDD were parallel. However, the mixturedose-response curves were significantly shifted to the rightof the TCDD dose-response curves by 1.3- to 1.8-fold as illustratedby LD₅₀ values. Following exposure to the mixture or TCDD, LD₅₀sfor lake trout early life stage mortality were 97 (89–110)pg TE/g egg and 74 (70–80) pg TCDD/g (LD₅₀, 95% fiduciallimits) and for rainbow trout were 362 (312–406) pg TE/gegg and 200 (148–237) pg TCDD/g egg. These data suggestthat TCDD-like congeners act via a common mechanism to causetoxicity during trout early development, but may not act strictlyadditively when combined in a mixture of TCDD- and non-TCDD-likecongeners at ratios found in Great Lakes fish. The deviationfrom additivity, however, is less than current safety factorsof 10-fold commonly applied in ecological risk assessments,providing support for the continued use of a TE additivity modelfor assessing risk posed by complex mixtures of PCDDs, PCDFs,and PCBs to fish.     

The Developmental Toxicity of Ethylene Glycol Diethyl Ether in Mice and Rabbits

Timed-pregnant CD-1 outbred Albino Swiss mice and New ZealandWhite rabbits were dosed by gavage with ethylene glycol diethylether (EGdiEE) in distilled water during major organogenesis.Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50,150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19(0, 25, 50, or 100 mg/kg/day). Maternal clinical status wasmonitored daily during treatment. At termination (gd 17, mice;gd 30, rabbits), confirmed-pregnant females (22–24 pergroup, mice; 26–32 per group, rabbits) were evaluatedfor clinical status and gestational outcome; each live fetuswas examined for external, visceral, and skeletal malformations.In mice, no maternal mortality was observed, but maternal bodyweight gain during gestation and treatment, and at terminationwas reduced at 1000 mg/kg/day. The reduction of maternal bodyweight gain during gestation was secondary to embryo/fetal toxicity,i.e., reduced gravid uterine weight as a consequence of decreasedlitter size and fetal weight. The no-observed adverse effectlevel (NOAEL) for developmental toxicity was 50 mg/kg/day. At150 mg/kg/day the number of litters of mice with malformed fetuseswas increased. At 500 mg/kg/day fetal body weight was reduced,and malformation incidence was significantly increased. Exencephalyand fused ribs were observed most often. In rabbits, maternalbody weight was unaffected by treatment even though 6% maternalmortality was observed at 100 mg/kg/day. The developmental NOAELwas 25 mg/kg/day. Malformations were increased at 50 mg/kg/day,short tail, small spleen, fused sternebrae, and fused rib cartilagewere observed most often. In summary, oral administration ofEGdiEE to mice and rabbits during organogenesis produced profoundadverse developmental effects even in the absence of significantmaternal toxicity. Developmental effects in rabbits were morevaried.     

Surgical anatomy of the singular nerve*

The course of the posterior ampullary (singular) nerve has been studied in 30 preserved human temporal bones. In 17 dissections (57%), the nerve was readily accessible in the floor of the round window niche without undue risk to the round window membrane or the ampulla of the posterior semicircular canal. In 5 bones (16%), the nerve was closely related to the round window membrane and could not have been approached without significant risk of damage to the membrane. In 8 (27%), the nerve ran more or less directly medially to the internal auditory meatus without entering the round window niche. The ampulla of the posterior semicircular canal would therefore have been at risk if the nerve were approached surgically. Keywords anatomy singular neurectomy     

Inability of the Signal-Averaged Electrocardiogram to Determine Risk of Arrhythmia Recurrence in Patients with Implantable Cardioverter Defibrillators

Signal-averaged electrocardiography has been used to identify patients at risk for arrhythmic death after myocardial infarction. Since patients with implantable cardioverter defibrillators (ICDs) are at high risk for arrhythmic events, they should also be expected to have a high incidence of abnormal signal-averaged electrocardiograms (SAECGs). However, whether the SAECG can discriminate patients who will have arrhythmia recurrence and receive appropriate ICD shocks from those who will have no recurrence and no shocks is unknown. This study examines the usefulness of the SAECG to separate appropriate users from non-users of the ICD. Fifty patients with ICDs participated in this study. Those who received a shock preceded by symptoms, a shock without preceding symptoms but with electrocardiographic documentation of ventricular fibrillation or ventricular tachycardia, or a shock while asleep were classified as ICD users. All other patients were classified as nonusers. The SAECG was classified as normal if the QRS duration on the standard electrocardiogram was less than or equal to 110 msec and if the total filtered QRS duration was less than 120 msec, the root-mean square voltage of the terminal 40 msec was greater than 25 muV, and the terminal low amplitude signal duration measured less than 38 msec. The SAECG was classified as abnormal if the QRS duration on the standard electrocardiogram was less than or equal to 110 msec and any one of these three criteria were outside the "normal range." The SAECG was classified as indeterminate if the QRS duration on the standard 12-lead electrocardiogram was greater than 110 msec. For the entire group of 50 patients, 8 (16%), 12 (24%), and 30 (60%) had normal, abnormal, and indeterminate SAECGs, respectively. Of the 22 ICD users, 1 (5%), 5 (23%), and 16 (73%) patients had normal, abnormal, and indeterminate SAECGs, respectively. Of the 28 ICD nonusers, 7 (25%), 7 (25%), and 14 (50%) patients had normal, abnormal, and indeterminate SAECGs, respectively. ICD users had lower left ventricular ejection fractions (P = 0.0002), a higher incidence of ventricular tachycardia (P = 0.04), prior exposure to a greater number of antiarrhythmic drugs (P = 0.04), and a lower likelihood for survival (P = 0.02) compared to the ICD nonusers. There was no statistically significant difference between the ICD users and nonusers as stratified by SAECG classification regardless of whether or not the interminate studies were included or excluded from the analysis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0,600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widelyused as an industrial solvent) vapors, 6 hr/day, 7 days/week(6–19 days of gestation (DG) for rats; 6–17 DG formice). Body weights of pregnant rats in the 5000 ppm group werereduced at euthanization. There were no effects on the percentageof live rat fetuses/litter or on the fetal sex ratio. Fetalbody weight was significantly reduced for the 5000 ppm group,but the incidence of abnormalities was not increased. Mice inthe 1800 and 5000 ppm groups were sedated during exposure; approximately27% of the mice in the 5000 ppm group died. Mean body and uterineweights of mice were reduced for the 1800 and 5000 ppm groupsat euthanization (18 DG), but adjusted maternal weight gainwas not affected at 1800 ppm. There was a reduction in the percentageof live fetuses/litter for the mice in 1800 and 5000 ppm groups(95% resorptions in the 5000 ppm group). Fetal weight and sexratio in mice were not affected. An increase in the incidenceof reduced sternebral ossifications was correlated to THF concentration,although differences between groups were not statistically significant.There were no increases in the incidences of other malformationsor variations. These results suggest that THF may be embryotoxicin mice, but if the conceptus survives, development as assessedby this experimental design continues in a normal fashion. Theno-observable-adverse-effect level (NOAEL) for maternal toxicitywas 1800 ppm in both rats and mice. The NOAEL for developmentaltoxicity was 1800 ppm in rats and 600 ppm in mice.     

Diabetes and Multiple Stents Independently Double the Risk of Short-term Revascularization

Several studies show worse outcome for diabetic patients after percutaneous transluminal coronary angioplasty (PTCA). There are relatively few studies evaluating outcome in the modern era of coronary stenting. We compared the incidence of death, myocardial infarction (MI), and repeat target lesion revascularization (RTLR) by PTCA or coronary artery bypass grafting (CABG) over a 6-month follow-up in 110 diabetic and 400 nondiabetic patients receiving Palmaz-Schatz stents. All patients received aspirin/ticlopidine and stents were deployed using high-pressure inflations. Seventy-five (68.2%) diabetic patients and 272 (68%) nondiabetic patients had single stents, while 35 (31.8%) diabetic and 128 (32%) nondiabetic patients had multiple stents (≥ 2stents in the same vessel). The success rate and acute major complications were not significantly different between diabetic and nondiabetic patients. There was also no significant difference in death, MI, and repeat PTCA between these two groups. Diabetic patients underwent CABG more frequently than nondiabetic patients (12.7% vs 3.2%, respectively, P =0.001) and diabetic patients also had RTLR more frequently than nondiabetic patients (25.5% vs 12.8%, respectively, P = 0.002) during 6-month follow-up. Multivariate analysis showed that diabetes and multiple stents independently contributed to the 6-month RTLR rate. Coronary stenting in diabetic patients can be carried out with a high success rate and low incidence of acute major complications. The presence of diabetes mellitus and multiple stent placement significantly increase the incidence of repeat target lesion revascularization.     

Humoral responses in mice following vaccination with DNA encoding glutathione S-transferase of Fasciola hepatica: effects of mode of vaccination and the cellular compartment of antigen expression

The humoral responses in mice following vaccination with DNA constructs encoding Fasciola hepatica glutathione S-transferase (GST) have been evaluated. GST47 cDNA was subcloned into two DNA vaccine vectors, VR1012 and VR1020, which direct expression to the cytoplasmic and extracellular compartments, respectively. Expression was confirmed by transfection into COS 7 cells. Groups of mice were vaccinated with these constructs, by either intramuscular injection with the VR1012-or VR1020-based constructs, or intradermal vaccination (with a gene gun) with the VR1020-based construct. Vaccination with the construct designed for secretion resulted in an increased humoral response compared to vaccination with the nonsecretory construct. The level of the total humoral response after vaccination with the secretion construct was not dependent on the route of vaccination. However, the isotype profile of the response differed between the groups; intramuscular vaccination with the construct directing cytoplasmic expression yielded an immuoglobulin (Ig)G2a dominant (Th1-type) response, intradermal vaccination with the secretory construct a IgG1/IgE dominant (Th2-type) response, and intramuscular vaccination with the secretory construct a mixed isotype response. These results demonstrate that the immunogenicity of a DNA vaccine based on Fasciola GST, as well as the isotype of the response against GST, is determined by the mode of vaccine administration.     

Carcinogenic Potential of Gasoline and Diesel Engine Oils

Used gasoline engine oils are carcinogenic in mouse skin andmutagenic in Salmonella. The toxicity of fresh gasoline engineoils and that of fresh and used diesel engine oils are lesswell defined. The present studies examined the dermal carcinogenicpotential of a series of fresh and used oils from both gasolineand diesel engines. The used oils represented a variety of operatingconditions. The objective of the study was to assess the potentialcarcinogenic hazards associated with exposure to these materials.The majority of the used gasoline engine oils tested were carcinogenicalthough one oil, collected after a relatively short drainageinterval, was inactive in the dermal carcinogenesis bioassay.Additionally, polycyclic aromatic hydrocarbon (PAH) concentrationswere elevated in the used oils in comparison to the fresh oils.The fresh gasoline engine oils and both the fresh and used dieselengine oil samples were noncarcinogenic, and there was littleevidence of elevated PAH levels in the used diesel engine oils.The carcinogenic potency of used oils from gasoline engineswas related to drainage interval, but other factors such ascontribution of the fuel due to blowby and driving cycle mayalso have been important. The used diesel engine oils were notcarcinogenic even after extended use.     

Glucagon releasing activity of a cyclic peptide related to somatostatin

A possible benefit of creating smaller and more rigid active analogs of somatostatin is the discovery of compounds which selectively inhibit the secretion of insulin, glucagon or growth hormone. A series of cyclic tetrapeptide analogs related to somatostatin was synthesized, and one member of this series was found to cause an unexpected stimulation of glucagon secretion while having little if any effect on either insulin or growth hormone secretion. A sustained increase in plasma glucose levels was also observed. Two possible modes of action are proposed.