Newer aspects of antiarrhythmic drug development: Introduction

Although cardiac arrhythmias remain a serious clinical problem in many patients with heart disease, the exact role of antiarrhythmic drug therapy is currently under intense evaluation. Within the last several years it has become clear that there are significant risks as well as potential benefits associated with existing agents. Ongoing studies in large patient populations should help determine the benefit/risk ratio of traditional therapy. Regardless of the outcome of these trials, current electrophysiological dogma will have to be re-evaluated and newer concepts evolve for drug development to make further progress. The goal of this symposium is to exchange information among basic and clinical investigators so as to facilitate the emergence of novel electrophysiological concepts that will form the basis for future generations of antiarrhythmic drugs.     

A Randomized Pilot Study of Behavioral Treatment to Increase Calorie Intake in Toddlers With Cystic Fibrosis

This pilot study examined a behavioral treatment to increase calorie intake in toddlers with cystic fibrosis. Eight toddlers were randomly assigned to behavioral plus nutrition (BEH) or nutrition intervention (NTR) conditions. Calorie intake and weight were measured at pre- and posttreatment. The BEH group showed a trend for changes in calorie intake pre- to posttreatment (p = .07; 40% increase). Results for the BEH and NTR groups did not differ significantly. Most participants achieved weight gains consistent with normal growth. Seventy-five percent had not shown this pattern during the year prior to intervention. These results support the feasibility and potential for behavioral interventions in this age group.     

Regional differences in endothelin converting enzyme activity in rat brain: inhibition by phosphoramidon and EDTA.

1. It has been demonstrated previously that conversion of big endothelin-1 (bET-1) to endothelin-1 (ET-1) is inhibited in vitro and in vivo by phosphoramidon. In addition, ET-1 binding sites and mRNA have been shown within the brain. Here we expand upon our previous observation that rat brain contains phosphoramidon-inhibitable endothelin converting enzyme (ECE) and show that this activity is not uniformly distributed throughout the brain. 2. ECE activity was detected by a bioassay which depended upon the 10,000 fold difference in potency between bET-1 and ET-1 as stimulants of guanosine 3':5'-cyclic monophosphate (cyclic GMP) accumulation in kidney epithelial (PK1) cells of the pig. Data were confirmed by specific enzyme-linked immunosorbent assay (ELISA) employing antibody directed against ET-1/3(17-21). 3. Following homogenization of the whole brain and ultracentrifugation the 100,000 g pellet contained greater than 4 times more ECE activity than the cytosol. Washing of the pellet with KCl (1 M) and extraction with the detergent CHAPS (20 mM) revealed a phosphoramidon-inhibitable ECE within the residual particulate fraction (nominally classified as the cytoskeletal fraction). Phosphoramidon (IC50, approx. 5 microM) or EDTA inhibited the conversion of bET-1 to ET-1 by the cytoskeletal fraction of rat brain by more than 60%.2+ 4. Following dissection of rat brain into olfactory bulb, cerebral cortex, striatum, hippocampus, cerebellum, midbrain (including thalamus), hypothalamus and medulla oblongata (including pons) the greatest ECE was detected in the hypothalamus and medulla oblongata.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coma arousal procedure: A therapeutic intervention in the treatment of head injury

This study reports on the efficacy of a 'coma arousal procedure'. This procedure involved a programme of vigorous sensory stimulation administered to comatose patients by relatives using Comakits. An experimental group of 12 severely head-injured patients received the coma arousal procedure while a matched control group did not. Total duration of coma and weekly Glasgow Coma Scale Scores were recorded for the two groups. Results indicate that the total duration of coma was significantly shorter and that coma lightened more rapidly for the experimental group.     

Nonheme iron in sickle erythrocyte membranes: association with phospholipids and potential role in lipid peroxidation

Previous studies documented the abnormal association of heme and heme proteins with the sickle RBC membrane. We have now examined RBC ghosts and inside-out membranes (IOM) for the presence of nonheme iron as detected by its formation of a colored complex with ferrozine. Sickle ghosts have 33.8 +/- 18.2 nmol nonheme iron/mg membrane protein, and sickle IOM have 4.3 +/- 3.0 nmol/mg. In contrast, normal RBC ghosts and IOM have no detectable nonheme iron. The combination of heme and nonheme iron in sickle IOM averages nine times the amount of membrane- associated iron in normal IOM. Kinetics of the ferrozine reaction show that some of this nonheme iron on IOM reacts slowly and is probably in the form of ferritin, but most (72% +/- 18%) reacts rapidly and is in the form of some other biologic chelate. The latter iron compartment is removed by deferoxamine and by treatment of IOM with phospholipase D, which suggests that it represents an abnormal association of iron with polar head groups of aminophospholipids. The biologic feasibility of such a chelate was demonstrated by using an admixture of iron with model liposomes. Even in the presence of tenfold excess adenosine diphosphate, iron partitions readily into phosphatidylserine liposomes; there is no detectable association with phosphatidylcholine liposomes. To examine the bioavailability of membrane iron, we admixed membranes and t-butylhydroperoxide and found that sickle membranes show a tenfold greater peroxidation response than do normal membranes. This is not due simply to a deficiency of vitamin E, and this is profoundly inhibited by deferoxamine. Thus, while thiol oxidation in sickle membranes previously was shown to correlate with heme iron, the present data suggest that lipid peroxidation is related to nonheme iron. In control studies, we did not find this pathologic association of nonferritin, nonheme iron with IOM prepared from sickle trait, high-reticulocyte, postsplenectomy, or iron-overloaded individuals. These data provide additional support for the concept that iron decompartmentalization is a characteristic of sickle RBCs.     

MRI of pancreatic gastrinomas.

Pancreatic islet cell tumors are often small and multiple, and preoperative diagnosis can be difficult. In a woman with hypergastrinemia, angiography and CT each depicted a solitary lesion. Magnetic resonance images, acquired using fat suppression, fast spin echo, and contrast material injection, depicted seven separate lesions, which were surgically confirmed.     

Gadoteridol dose dependence in MR imaging of a liver abscess model

A necrotic liver abscess model was studied with magnetic resonance (MR) imaging at 1.5 T before and after intravenous administration of gadoteridol at doses of 0.1, 0.25, and 0.5 mmol/kg in 24 rabbits. Enhancement characteristics and lesion delineation were assessed with both breath-hold and non-breath-hold imaging techniques. Lesion delineation, as assessed both by signal intensity measurements and evaluations by two image readers blinded to imaging technique, was greatest on high-dose (0.5 mmol/kg) breath-hold images. Lesion rim enhancement was seen consistently only on postcontrast images obtained at a dose of 0.5 mmol/kg and progressed with time after injection of contrast material.     

The clinical course of Felty's syndrome compared to matched controls

In a cohort of 919 patients with definite or classic rheumatoid arthritis followed prospectively since 1966, we identified 36 patients with Felty's syndrome (FS). Their clinical course was compared to that of 72 matched controls from the same cohort. Patients with FS had more extraarticular features and more infections than control patients. The presence of joint erosions, serial Lansbury indices, and death rates were similar in both groups. Cardiovascular disease was the commonest cause of death in both groups, accounting for 32% of all deaths. Sepsis accounted for 10% of deaths in the group with FS and 13% of deaths in the controls.