Protein components specifically associated with prespliceosome and spliceosome complexes.

We have carried out a systematic analysis of the protein composition of highly purified mammalian spliceosomes. We show that > 30 distinct proteins, including 20 previously unidentified components [designated spliceosome-associated proteins (SAPs)], are specifically associated with the spliceosome in a salt-resistant complex. In contrast to these spliceosome-specific proteins, we show that hnRNP proteins are not tightly associated with purified prespliceosome and spliceosome complexes. The splicing factor U2AF65, U1 snRNP-specific proteins, and several SAPs are present in the earliest prespliceosome complex (E). A set of 10 proteins is then added to the first ATP-dependent prespliceosome complex (A), and concomitantly, a significant decrease in the level of U2AF65 is observed. The fully assembled spliceosome is formed by the addition of 12 proteins in a reaction that requires ATP and both the 5' and 3' splice sites.     

Adverse mortality experience of a southwestern American Indian community: overall death rates and underlying causes of death in Pima Indians

As part of an ongoing epidemiologic study, the death rate and causes of death during 1975 through 1984 were determined in Pima Indians who resided in the Gila River Indian Community (GRIC) in 1965 and later. Death certificates were available for 677 of the 681 deaths. In 78% of the deaths, the underlying cause recorded on the death certificate agreed with the cause determined after review of all available relevant records. The age- and sex-adjusted average annual death rate for the GRIC population (1639/100,000) was 1.9 times (95% CI 1.7-2.0) the 1980 rate for the U.S. all races (878/100,000). In Pima males, whose death rate was substantially higher than that of Pima females, the age-adjusted death rate was 2.3 times that in U.S. males, all races. Moreover among males 25-34 years of age, the Pima death rate was 6.6 times that for the U.S. all races. Diseases of the heart and malignant neoplasms caused 59% of U.S. deaths in 1980, but only 19% of GRIC deaths. By contrast, the age- and sex-adjusted mortality rate in the GRIC Pima was 5.9 times the rate of the U.S. all races for accidents, 6.5 times for cirrhosis, 7.4 times for homicide, 4.3 times for suicide, and 11.9 times for diabetes. Tuberculosis and coccidioidomycosis were important causes of death in the Pima, for whom infectious diseases was the tenth leading cause of death. The findings indicate that programs to improve the adverse mortality experience of the GRIC population should emphasize factors related to fatal accidents, alcoholic cirrhosis, homicide, suicide, diabetes mellitus, and infectious diseases. Young Pimas, especially the males, should be the primary focus of such preventive efforts. These findings and recommendations probably apply to many Native American populations.     

The comparison of trends in perinatal mortality in small areas

Year to year changes in perinatal mortality rates for small populations are difficult to interpret. Because local rates are based on small numbers of events, they are subject to apparently large fluctuations. A technique for analysing trends in mortality, for detecting changes in trends and comparing variations in trends between areas is described. It is illustrated by an analysis of perinatal mortality rates for Area Health Authorities in the West Midlands Region of England from 1974-1981, but the same techniques could be used to analyse trends at other times and in other places.     

Venous arterialization for erectile impotence

Revascularization of the corporal bodies in arteriogenic impotence can be accomplished by means of a venous arterialization procedure as described by Ronald Virag. This surgical approach and early results are detailed in this article.     

The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats

Although it has been demonstrated that many of the behavioral responses to psychomotor stimulants are gender dependent and hormonally sensitive, few studies have examined the possibility that the estrous cycle interacts with drug reinforcement in laboratory animals. The present experiment assessed the effect of the estrous cycle on two aspects of cocaine self-administration behavior: the breaking point on a progressive ratio (PR) schedule and the rate of cocaine intake on a fixed ratio one (FR1) schedule. On the PR schedule, the first lever response produced a drug infusion. Subsequent response requirements escalated with each injection until the behavior extinguished. Breaking points were defined as the final ratio completed. On a FR1 schedule, the estrous cycle had no effect on the rate of drug intake. On a PR schedule, female rats reached higher breaking points during estrus than during other stages of the estrous cycle. Furthermore, female rats displayed higher breaking points than male rats. It appears that the estrous cycle influences an animal's motivation to self-administer cocaine.     

Sodium channel block by a potent, new antiarrhythmic agent, transcainide, in guinea pig ventricular myocytes

Transcainide is a new lidocaine analog that has been shown to suppress a range of cardiac arrhythmias in an initial clinical trial. We have evaluated the effects of transcainide on sodium channel current in guinea pig ventricular myocytes using the whole-cell patch-clamp technique. Reduction of sodium current by transcainide was concentration dependent, with an ED50 of approximately 0.5 microM (n = 9). This reduction of the sodium current exhibited little use dependence, and block did not accumulate even after 10-Hz pulse trains. Moreover, little or no recovery from block was observed even when cells were hyperpolarized to -160 mV for 1 min. We observed no reversal of sodium channel block after superfusing cells up to 1 h in drug-free solution. Thus, transcainide, unlike many other clinically useful antiarrhythmic agents, blocked sodium channels with very little time dependence or voltage dependence. These novel electrophysiological properties of transcainide may endow the agent with a unique spectrum of efficacy against certain arrhythmias. At the same time, the great potency of transcainide and its lack of reversibility, at least within an hour, mandate that the drug should be used with great caution.     

Heartburn and gastro-oesophageal reflux.

Heartburn is a readily recognised symptom which half the British population have experienced at some time, and a fifth have frequently. It is the predominant symptom of gastro-oesophageal reflux, although less than two thirds of sufferers have endoscopically visible oesophagitis. Heartburn can also be associated with peptic ulcers or functional dyspepsia. Several changes in oesophageal function contribute to the syndrome of gastro-oesophageal reflux, the most important being inadequacy of the complex mechanism at the gastro-oesophageal junction. Understanding the various functional failures offers a better understanding of the therapeutic possibilities.     

Heroin self-administration in rats under a progressive ratio schedule of reinforcement

Heroin self-administration behavior under a progressive ratio (PR) schedule of reinforcement was evaluated in rats. The schedule was designed to restrict drug intake, minimize opiate dependency, and quantify the number of responses emitted (final response ratio) in order to receive a limited number of heroin infusions. Final ratios were found to be stable and did not increase with chronic (31 days) PR reinforcement. The ability of the PR schedule to detect changes in heroin reinforcement was demonstrated by evaluating the effect of naltrexone pretreatment and unit dose alteration on final ratios. Naltrexone (0.4 mg/kg) reduced final ratios and an inverted U dose-response relationship was established for the unit heroin doses 12.5–100 µg/injection. Maximal final ratios occurred with 50 µg/injection heroin reinforcement. This PR schedule may provide a useful method for evaluating the effects of pharmacological manipulations or lesions on opiate reinforcement.