Aims To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. Methods and results This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat ( n = 537) and non-febuxostat groups ( n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively ( P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592–0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562–0.987; P = 0.041). Conclusion Febuxostat lowers uric acid and delays the progression of renal dysfunction. Registration ClinicalTrials.gov (NCT01984749).

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C–lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50–0.86; P =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37–0.98; P =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18–0.79; P =0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. Conclusions: LDL-C–lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp . Unique identifier: UMIN000001988.

BAG6 (also known as BAT3/Scythe) is a ubiquitin-like protein that is thought to participate in a variety of seemingly unrelated physiological and pathological processes, such as apoptosis, antigen presentation and the T-cell response. Recent studies have shown that BAG6 is essential for the quality control of aggregation-prone polypeptide biogenesis. It forms part of a complex that determines the fate of newly synthesized client proteins for membrane insertion, ubiquitin-mediated degradation and/or aggregate formation. A biologically relevant transmembrane protein family has recently been shown to be a major client of BAG6, suggesting that many of the known diverse BAG6 functions can be interpreted by BAG6-mediated control of membrane protein biogenesis. In this review, we summarize the current understanding of the physiological roles of BAG6 with a particular focus on quality control for nascent chain polypeptides.

Uroguanylin activates the intestinal and possibly the renal guanylate cyclase C receptor, and stimulates Cl- secretion. We developed a sensitive radioimmunoassay (RIA) for human uroguanylin and measured its concentration in the urine and plasma. Twenty-four-hour urinary excretion of immunoreactive (ir-) uroguanylin for persons with a high-salt diet (10 g/day) was 137.8 +/- 14.4 pmol/day, significantly higher than that for persons with a low-salt diet (7 g/day, 95.1 +/- 16.3 pmol/day, P < 0.05). There were significantly positive correlations between the urinary excretion of ir-uroguanylin and Na+, Cl-, K+ or cyclic GMP (cGMP). We demonstrated the presence of messenger RNA of guanylate cyclase C in the medulla of human kidney. The concentration of plasma ir-uroguanylin significantly correlated with that of serum creatinine (r = 0.71, P < 0.001). Biologically active uroguanylin-16 accounted for 99% of the endogenous uroguanylin molecules in normal urine and 60% in plasma, the remainder being the 10 kDa precursor. The precursor content increased in the urine and plasma as the severity of renal impairment increased. These findings suggest that bioactive uroguanylin-16 is involved in the regulation of electrolyte homeostasis and that the kidney participates in the metabolism and excretion of uroguanylin.