Gene encoding the catalytic subunit p110beta of human phosphatidylinositol 3-kinase: cloning, genomic structure, and screening for variants in patients with type 2 diabetes.

Phosphatidylinositol (PI) 3-kinase is a key signaling molecule in insulin-stimulated glucose transport. Therefore, we investigated the catalytic subunit p110beta, of human PI 3-kinase as a candidate gene for type 2 diabetes. Human p110beta gene was cloned from the placental genomic library. All 22 exons, intronic regions flanking the exons and 1.5 kb of the proximal/5' region of the p110beta gene, were screened for variants by single-strand conformation polymorphism analysis in 79 Finnish patients with type 2 diabetes . Allele frequencies of the variants were also determined in 77 nondiabetic control subjects. No variants were found in exons in diabetic patients. However, we identified two nucleotide polymorphisms in the proximal/5' region of the p110beta gene and a variation in the number of 2-bp repeat sequence (TA)n in intron 4. The allele frequencies did not differ between diabetic and control subjects. Our results may indicate that the catalytic subunit p110beta of PI 3-kinase plays such a fundamental role in the insulin-signaling pathway that structural variants are not likely to exist in that gene. The importance of the polymorphisms in the proximal/5' region of the p110beta gene for insulin signaling remains to be determined.

Long-term thresholds of nonsteroidal permanent pacing leads: a 5-year study.

The present commercial market supports many nonsteroidal endocardial pacing leads of differing construction. In order to compare the performance of these configurations, we studied the long-term pacing properties of three representative lead types by randomized clinical trial in 99 patients undergoing a first elective VVI implant. Thirty-one patients received sintered platinum leads, 36 activated pyrolytic carbon leads, and 32 vitreous carbon leads. All received generators capable of noninvasive threshold testing. Acute sensing parameters were R wave amplitude and ST segment elevation measured from the endocardial electrogram. Noninvasive voltage thresholds were measured at implantation, 2 days, 1, 3, and 6 months, and yearly thereafter for 5 years. There were no significant differences between leads in pacing or sensing capabilities at implantation. All three demonstrated similar increases in thresholds, peaking at 1 month, then falling to a plateau by 6 months and did not vary significantly thereafter. There were no significant differences in thresholds between leads during 5 years of follow-up. The lowest mean threshold at 5 years was 0.93 V at 0.5 ms. This study suggests that: (1) although these lead types all perform well, none offers any particular clinical advantage over another; (2) the degree of early threshold peaking precludes immediate postimplant output reduction, but later thresholds are sufficiently low to enable reductions in pacing output; (3) safe low energy pacing requires greater attention to the lead-generator combinations; (4) data obtained at subsequent annual follow-up provided no additional useful clinical information to that obtained at 1 year; and (5) in the absence of other differences, cost can be the deciding factor in lead selection.