A nonconditional mutant of Rous sarcoma virus containing defective polymerase.

A nonconditional mutant of Rous sarcoma virus (RSV) cd SE52dPR-C (SE52d), which is a recombinant between PR-RSV-C and RAV-0, has been isolated. It is shed from a clone of transformed quail cells, but is unable to exogenously infect or transform any other avian cells. It contains subgroup C envelope glycoproteins and the internal structural protein p27o characteristic of RAV-0. SE52d virions contain no detectable polymerase activity as measured in either an endogenous reaction or after addition of exogenous template. The genome of SE52d contains a deletion of approximately 10% of the genome as compared to PR-RSV, which can be localized between about 0.7 and 0.8 of the genome length from the 3′ terminus of the RNA. The deletion includes about 30% of the polymerase gene. The virions contain no α or β polymerase subunits (95,000 and 65,000 daltons), but do appear to have a small amount of a new protein species of about 57,000 daltons which precipitates with antibody to viral polymerase.     

High-density lipoproteins in myocardial infarction survivors.

Subjects with existing coronary heart disease and those with many of the conditions associated with increased risk of coronary disease have reduced levels of high-density lipoprotein (HDL) cholesterol. Since HDL cholesterol is only one index of HDL composition, a reduction of HDL cholesterol could reflect a change in HDL composition and/or a decrease in all HDL constituents. Therefore the present studies assessed the major apolipoproteins of HDL, A-I and A-II, in addition to HDL cholesterol in 90 male myocardial infarction (MI) survivors and their lipid-matched male controls. The MI survivors had significantly lower (p < 0.01) A-I (112 ± 2 mg/dl, mean ± SEM), A-II (29 ± 1 mg/dl), and HDL cholesterol (39 ± 1 mg/dl) than the lipid-matched control group (A-I, 121 ± 2; A-II, 33 ± 1; HDL cholesterol, 43 ± 1) and than a population-based male control group (n = 172; A-I, 121 ± 2; A-II, 33 ± 1; HDL cholesterol, 45 ± 1). The HDL cholesterol/A-I ratio in the MI survivors was slightly lower than the ratio in the lipidmatched control group but significantly lower (P < 0.02) than that in the population-based control group. The HDL cholesterol of both control groups was significantly negatively related to log triglyceride (r = ?0.43). Similarly the HDL cholesterol of the MI survivors was inversely correlated with log triglyceride (r = ?0.51), but the slope of this relationship was significantly steeper in the MI survivors. These results are consistent with a relative decrease of HDL in MI survivors over and above that attibutable to their increased triglyceride levels.     

Characteristics of survivors of exertion- and nonexertion- related cardiac arrest: Value of subsequent exercise testing

Ninety ambulatory patients previously resuscitated from out-of-hospital ventricular fibrillation underwent treadmill exercise testing an average of 11.5 months after the episode. The level of physical activity immediately before cardiac arrest was known in 86 patients: 23 (27%) had had ventricular fibrillation in association with exertion and 63 (73%) while performing low level activity. Prodromal chest pain and evidence of acute myocardial infarction occurred in a similar proportion of both activity groups. Subsequent exercise test results showed few differences between the groups. Angina occurred in only 11 patients and exercise evoked “ischemic” S-T change in less than half of each group. More of the patients who had collapsed during nonexertional activities had exercise-evoked complex ventricular arrhythmias than did patients who had collapsed during exertion: 33 (52%) versus 6 (26%), respectively (p < 0.05).The 90 patients were followed up for 2 or more years. At 24 months of follow-up, there were 27 deaths of which 19 were due to unexpected cardiac arrest. Only 2 findings on exercise testing were associated with subsequent fatal events. Seven of 11 patients (64%) who had angina during testing had cardiac arrest or died, compared with 20 patients (25%) who had stopped for other reasons (p < 0.01). Failure of systolic arterial pressure to rise 10 mm Hg or more during the test was also associated with poor survival: respective mortality at 2 and 4 years was 54 and 69% in those with this abnormal response, compared with 26 and 42% at 2 and 4 years in those whose pressure rose normally (p < 0.004).In the majority of patients ventricular fibrillation developed at low activity levels, and no characteristics were found unique to those who collapsed during exertion. Routine exercise testing was of limited value in the assessment of patients previously resuscitated from cardiac arrest. Exerciseevoked angina and systolic hypotension were highly associated with outcome; however, their ability to predict survival for individual patients was only modest.     

Exogenous estrogens attenuate dietary hypercholesterolemia and atherosclerosis in the rabbit

The effect of exogenous estrogens upon the response to dietary cholesterol was tested in New Zealand White rabbits. Cholesterol-fed, untreated rabbits had a 10-fold increase in plasma cholesterol in 12 wk. The major increase of cholesterol occurred in very low density lipoproteins (VLDL, 43.5-fold) followed by intermediate density lipoproteins (IDL, 26-fold) and low density lipoproteins (LDL, 6-fold) with no change in high density lipoproteins (HDL). These diet induced changes were markedly attenuated in the estrogen treated animals, in whom plasma cholesterol increased only 5-fold. This increase was distributed among LDL (6-fold), IDL (7.5-fold), and VLDL (9-fold), similarly with no change in HDL. All the lipoproteins in both groups of animals were considerably enriched in cholesterol during cholesterol feeding as indicated by a high cholesterol/protein and cholesterol/triglyceride ratio. However, these ratios were lower in estrogen treated animals. There were no differences in the feed consumption, body weight or cholesterol absorption between the two groups of animals. Rabbits fed a cholesterol-rich diet but not treated with estrogen had well developed lesions in all parts of the aorta with higher content of cholesterol and phospholipids as compared to those injected with estrogen, whose aortas were completely clear of visible atherosclerosis. Equivalent total hypercholesterolemia was induced in other estrogen-treated rabbits by feeding twice the cholesterol dietary content (0.2%) as in nonestrogen-treated animals. Aortic atherosclerosis was far more evident in the latter, which had higher proportions of cholesterol-rich lipoproteins of d < 1.006 g/ml.     

Prolongation of cardiac refractory times in man by clofilium phosphate, a new antiarrhythmic agent

The electrophysiologic effects of clofilium phosphate, a new quaternary ammonium antiarrhythmic agent, were evaluated in 15 patients with a variety of cardiac dysrhythmias. Ten patients had ventricular dysrhythmias and five patients had supraventricular dysrhythmias. Clofilium was administered as a single bolus intravenously in doses ranging from 60 to 300 micrograms/kg during electrophysiologic testing. Blood pressure and heart rate were unchanged, and there were no significant side effects. Conduction time was unchanged in atrial tissue, ventricular tissue, atrioventricular node, and in the His-Purkinje system. QT intervals lengthened, atrial effective refractory period increased, and ventricular effective refractory period increased. The effective refractory period of the AV node was unchanged. Refractoriness of the bundle branches or His-Purkinje system was increased in eight patients. Inducible supraventricular arrhythmias were improved in four of four patients, and inducible ventricular arrhythmias were improved in at least five of nine patients. Clofilium is a model for an antiarrhythmic drug which should be useful in interrupting or suppressing reentrant arrhythmias because it increases refractoriness without major changes in conduction time.     

Lipid metabolism in pregnancy. VIII. Effects of dietary fat versus carbohydrate on lipoprotein and hepatic lipids and tissue triglyceride lipases

We have asked, is hypertriglyceridemia in the fed state in pregnancy due to intolerance to exogenous fat, accumulation of endogenous triglycerides, or accumulation of remnants of d < 1.006 lipoprotein metabolism? To answer these questions, we fed rat-free diets high in starch or sucrose, or diets containing fat or fat plus cholesterol to pregnant and nonpregnant rats for 12 days until gestational day 21 (term = 22 days). Blood was obtained 0, 4, or 8 hr after removal of food from the cages. Lipid concentrations were determined in chylomicrons and very low, low, and high density lipoproteins. Hypertriglyceridemia in pregnancy exists on both starch and sucrose containing fat-free diets and is exaggerated 4 and 8 hr after food is removed from the cage. The triglyceride rise occurs in d < 1.006 lipoproteins. With fat feeding, chylomicron triglyceride concentrations are not significantly elevated in pregnant rats, 0 or 8 hr postabsorptively despite greater food intake in pregnancy. In contrast, very low density lipoprotein (VLDL) triglyceride concentrations are elevated at all times following fat feeding in pregnant compared to nonpregnant animals. A significant contribution of lipoprotein remnants to the triglyceride rise in d < 1.006 lipoproteins seems unlikely since an isolated increase in VLDL cholesterol is not observed. No statistically significant accumulation of hepatic triglycerides occurs on any diet in pregnancy. Diet induced shifts in adipose tissue and muscle lipoprotein lipase activity are exaggerated in pregnancy while hepase in unaffected. Fetal weight is similar on all diets except sucrose where weight is reduced. Conclusions: Hypertriglyceridemia in fed pregnant rats is due to an increase in endogenous triglycerides. Remnant lipid accumulation does not appear to contribute to the endogenous hypertriglyceridemia. There is no intolerance to exogenous (dietary) fat. The results are compatible with an unimpaired delivery of exogenous fat to fat oxidizing tissues thereby maximizing glucose availability for fetal growth.     

Lp(a) lipoprotein: relationship to sinking pre-beta lipoprotein hyperlipoproteinemia, and apolipoprotein B.

To assess the relationship between the Lp(a) and the "sinking pre-beta" (d smaller than 1.006) lipoprotein, the concentration of Lp(a) was quantified by radial immunodiffusion and the presence or absence of sinking pre-beta was assessed by agarose electrophoresis in overnight fasting plasma samples from 485 adults, comprised of 320 with normal lipid levels, 48 with type IIa, 40 with type IIb, and 77 with type IV lipoprotein phenotypes. The median Lp(a) level was 7.6 mg/100 ml, 89% (433 of 485) having detectable Lp(a) levels. Twenty-two per cent (107 of 485) had detectable pre-beta lipoprotein in the d greater than 1.006 plasma fraction (sinking pre-beta). Of the sinking pre-beta positive plasma samples, 96% (102 and 107) exceeded the median Lp(a) level, and sinking pre-beta was detected in all 44 samples with an Lp(a) concentration exceeding 40 mg/100 ml. The relationship of Lp(a) and sinking pre-beta to lipoprotein phenotype was assessed. Compared to the normolipidemic group, the type IIa group had higher Lp(a) percentile values (p smaller than 0.02), whereas the IIb and type IV groups had significantly lower Lp(a) values than the normolipidemic group. Ninety-two per cent (296 of 320) of the normolipidemic subjects had detectable levels of Lp(a) and 22% (70 of 320) had detectable sinking pre-beta lipoprotein. Ninety-four per cent (45 of 48) of the type IIa plasmas had detectable Lp(a) levels and 27% (13 of 48) had sinking pre-beta lipoproteins. Contrasted with the IIa group, only 80% (32 of 40) of the IIb plasmas had detectable Lp(a) levels and 18% (7 of 40) had sinking pre-beta lipoprotein. In the type IV plasmas 78% (60 of 77) had detectable Lp(a) and 22% (17 of 77) had sinking pre-beta lipoprotein. Lp(a) or log Lp(a) levels were not correlated with apolipoprotein B levels (n = 485, r = 0.002 or 0.037, respectively). Furthermore, Lp(a) levels remained essentially constant in three subjects whose aprptein B levels were altered in response to pharmacological and/or dietary manipulation. A fourth subject had a 50% increase in Lp(a) but this change did not correlate with apoprotein B changes. Thus, these findings suggest that Lp(a) is metabolically independnet of low density lipoprotein even though it shares the same structural protein, apoprotein B.     

Anodal stimulation as a cause of pacemaker-induced ventricular fibrillation

A review of animal investigations suggests that pacemaker-induced ventricular fibrillation usually occurs at the anode, and in fact is difficult to evoke at the cathode. A search of the literature showed that every documented episode of pacemaker-induced ventricular tachycardia/fibrillation in humans has been with a bipolar electrode system. Since the problem most often occurs during temporary pacing associated with myocardial infarction, bipolar catheter electrodes should not be used for temporary pacing, and the use of unipolar (cathodal) pacing systems should increase the safety of electrical pacing.     

Iatrogenic pediatric hydroxocobalamin overdose

IntroductionHydroxocobalamin, a precursor molecule to vitamin B12, has emerged as the preferred empiric treatment for patients rescued from enclosed-space fires with concern for inhalational injury and potential concomitant cyanide toxicity. Limited data exist on the effects of hydroxocobalamin toxicity, particularly in pediatric patients.Case reportWe report a case of a healthy three-year old girl who was rescued from an apartment fire and electively intubated by prehospital providers. Due to concern for potential cyanide toxicity, she received 5 g (373 mg/kg) of intravenous hydroxocobalamin, an amount equivalent to one standard adult dose but over five times the appropriate weight-adjusted dose for this 13.4-kilogram child. On hospital arrival, patient was noted to have chromaturia and diffuse erythroderma without cutaneous burns. She was extubated 4 h after prehospital intubation and discharged home the following morning in good condition with persistent erythroderma. Skin color returned to normal within two days.DiscussionWe believe this to be the first reported case of iatrogenic pediatric hydroxocobalamin overdose for the treatment of suspected cyanide toxicity. Erythroderma and chromaturia are expected side effects of hydroxocobalamin, even at therapeutic levels. Along with minor airway burns, the only other finding was a transient and hemodynamically neutral bradycardia, which began shortly after prehospital intubation. As this bradycardia occurred prior to hydroxocobalamin administration, more likely culprits include vagal nerve stimulation from direct laryngoscopy, and sinoatrial muscarinic receptor stimulation caused by repeated doses of succinylcholine. In all, we were unable to appreciate any complications due to excess hydroxocobalamin administration.