Molecular insights into the normal operation, regulation, and multisystemic roles of K +

Long before the molecular identity of the Na+-dependent K+-Cl− cotransporters was uncovered in the mid-nineties, a Na+-independent K+-Cl− cotransport system was also known to exist. It was initially observed in sheep and goat red blood cells where it was shown to be ouabain-insensitive and to increase in the presence of N-ethylmaleimide (NEM). After it was established between the early and mid-nineties, the expressed sequence tag (EST) databank was found to include a sequence that was highly homologous to those of the Na+-dependent K+-Cl− cotransporters. This sequence was eventually found to code for the Na+-independent K+-Cl− cotransport function that was described in red blood cells several years before. It was termed KCC1 and led to the discovery of three isoforms called KCC2, KCC3, and KCC4. Since then, it has become obvious that each one of these isoforms exhibits unique patterns of distribution and fulfills distinct physiological roles. Among them, KCC3 has been the subject of great attention in view of its important role in the nervous system and its association with a rare hereditary sensorimotor neuropathy (called Andermann syndrome) that affects many individuals in Quebec province (Canada). It was also found to play important roles in the cardiovascular system, the organ of Corti, and circulating blood cells. As will be seen in this review, however, there are still a number of uncertainties regarding the transport properties, structural organization, and regulation of KCC3. The same is true regarding the mechanisms by which KCC3 accomplishes its numerous functions in animal cells

Rivaroxaban with or without aspirin in stable cardiovascular disease

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=−4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events