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Objective: To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers., Approach and Results: This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively., Conclusions: Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion., (© 2016 American Heart Association, Inc.)

Apolipoprotein B (apoB) has additional benefits over conventional lipid measurements in predicting future cardiovascular disease (CVD). We aimed to validate the clinical relevance of our equation to estimate apoB in a large-scale, prospective, community-based cohort study (Ansung-Ansan cohort study).A total of 9001 Korean subjects were assessed. We excluded subjects with history of CVD (n = 228), taking lipid-lowering medications (n = 51), and those whose outcome data were not available (n = 33). Finally, a total of 8713 subjects (4126 men and 4587 women) with a mean age of 52.2 years were enrolled and followed up biannually for a mean 8.1 years.At baseline, 24.9% of subjects were current smokers, 12.5% had diabetes, and 22.2% had hypertension. Incident case of CVD occurred in 600 of the study subjects (493 ischemic heart disease and 424 stroke). Independent variables included in the models were age, sex, waist circumference, current smoking, and presence of diabetes and hypertension. Both non-HDL cholesterol (HR per 1-SD [95% CI]; 1.13 [1.05-1.23], P = 0.002) and estimated apoB (HR per 1-SD [95% CI]; 1.14 [1.05-1.24], P = 0.001) were independently associated with the development of CVD; however, the LDL cholesterol level was not predictive of future CVD (HR per 1-SD [95% CI]; 1.07 [0.99-1.16], P = 0.08).Both non-HDL cholesterol and estimated apoB level were independently associated with the development of CVD. Because LDL cholesterol has limited value to predict incident CVD, we recommend calculating non-HDL cholesterol or apoB with our equation to predict risk of incident CVD in the general Korean population., Competing Interests: The authors have no conflicts of interest to disclose.

Purpose: To compare the effect and the treatment outcomes of bevacizumab and ranibizumab in the treatment of Type 1 retinopathy of prematurity (ROP)., Methods: This was a bicentered retrospective case series performed at institutional referral centers. Seventy-two eyes of 37 patients who had intravitreal injections of either bevacizumab or ranibizumab as the primary treatment for Type 1 ROP were included. Outcomes' measures included regression and recurrence of ROP, the surgical complications, and refractive errors at a corrected age of 1 year., Results: All but one eye in the bevacizumab group had retinal neovascularization and plus disease regression after anti-vascular endothelium growth factor treatment. Neither recurrence of ROP nor major ocular complications, including cataract, retinal detachment, and endophthalmitis occurred in any of the treated eyes. There were no significant differences in mean refractive errors between the patients treated with intravitreal injections of bevacizumab or ranibizumab at the corrected age of 1 year. A significantly higher chance of high myopia was noted in the bevacizumab group (P = 0.03)., Conclusion: Both bevacizumab and ranibizumab showed similar efficacy in the regression of ROP with minor mean refractive errors at 1 year of corrected age. However, high myopia was more prevalent in the bevacizumab-treated eyes.

Background: Drugs that selectively block nitric oxide synthase (NOS) 2 enzyme activity by inhibiting dimerization of NOS2 monomers have recently been developed., Methods and Results: To investigate whether selective inhibition of NOS2 is cardioprotective, rats were pretreated for 2 days with BBS2, an inhibitor of NOS2 dimerization, at 15 mg/kg SC. Isolated buffer-perfused hearts from treated (n=9) and control (n=7) hearts were subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion. NOS2 protein was upregulated in all hearts at the end of ischemia and of reperfusion; NOS2 enzyme activity was 60% lower in hearts from the treated animals. In the treated hearts, the increase in end-diastolic pressure was significantly attenuated at the end of ischemia, and the return of developed pressure at reperfusion was greater (P<0.05). Creatine kinase release at reperfusion was lower in treated hearts than in controls (P=0.02). At the end of ischemia and of reperfusion, myocardial ATP levels were significantly higher in the treated hearts than in controls (P<0.05). In the treated hearts under ischemic conditions, lactate content was higher and the lactate/pyruvate ratio was lower than in controls (P<0.05); GAPDH activity was higher; and G-3-P and aldose reductase activity were lower. At reperfusion, in the treated hearts, there was less histological damage and less apoptosis of cardiac muscle cells., Conclusions: Pretreatment with BBS2, a selective inhibitor of NOS2, improves contractile performance, preserves myocardial ATP, and reduces damage and death of cardiac myocytes during ischemia and reperfusion of isolated buffer-perfused rat hearts.

This study was conducted to demonstrate the burn-induced lung neutrophil deposition and damage in rats is affected by the nitric oxide (NO)-dependent downstream cGMP signaling. In experiment 1, 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ) was given (20 mg/kg i.p.) to specific pathogen-free Sprague-Dawley rats immediately postburn to suppress the guanylate cyclase (GC) activity. At 8 h after burn, blood was assayed for the peroxynitrite-mediated dihydrorhodamine 123 (DHR 123) oxidation and lung tissues were harvested for myeloperoxidase (MPO) determination and histological studies. Pulmonary microvascular dysfunction was quantified by measuring the extravasations of Evans blue dye. In experiment 2, Sodium nitroprusside (SNP) was given (2 mM, i.p.) to elevate cGMP levels and ODQ (20 mg/kg, i.p.) or methylene blue (100 microM, i.p.) or saline was given. The animals were sacrificed 4 h after injection and lung tissues were harvested for iNOS mRNA study. The MPO activity in lung, blood DHR 123 oxidation level, and lung permeability increased up to 2-fold, 4-fold, and 2.5-fold after burn. Inhibition of GC by ODQ administration significantly decreased MPO activity, blood DHR 123 oxidation, and lung permeability by 55%, 66%, and 53%, respectively, and markedly decreased the thermal injury-induced perivascular and interstitial inflammatory cell infiltration and septum edema. The protective effects of ODQ were comparable to the use of selective iNOS inhibitor as demonstrated previously. Furthermore, ODQ decreased the burn or SNP-induced iNOS mRNA levels at 4 h after burn. These findings suggest that burn-induced lung dysfunction is mediated by the NO/cGMP system because it is abolished by application of either iNOS inhibitor or GC inhibitor. Also, the beneficial effect of ODQ is partly due to the attenuation of burn-induced iNOS expression by GC inhibition.

Background: A number of experimental studies have shown that increasing glucose use or decreasing accumulation of long-chain acyl carnitines (LCAC) protect ischemic hearts., Methods: To evaluate the relative importance of these two strategies in protecting ischemic myocardium, isolated rat hearts (n = 6 in each group) were paced at 300 bpm and subjected to 50 min of low-flow ischemia followed by 60 min of reperfusion. Buffer contained 0.4 m mol/l albumin, 0.4 m mol/l palmitate, and 70 mU/l insulin, and either normal glucose (5 m mol/l) (CON), high glucose (10 m mol/l total) (HG, known to increase glucose use), 5 m mol/l glucose and niacin (10 micromol/l) (NIA, known to increase glucose use and decrease LCAC) or carnitine (10 m mol/l) (CAR, known to increase glucose use and decrease LCAC). Separate groups of hearts were perfused in the presence of 10 micromol/l cytochalasin-B (CB), an inhibitor of insulin-sensitive glucose transporters., Results: Ischemic injury, as assessed by creatine kinase (CK) release was diminished by an average of 50% in HG, NIA, and CAR hearts, and the percentage recovery of left ventricular (LV) function with reperfusion was enhanced by approximately 20% compared with CON hearts (P < 0.05 for each comparison). Cytochalasin-B abolished all of the salutary effects. Long-chain acyl carnitines levels were higher in HG hearts compared with NIA- and CAR-treated hearts ( P < 0.05), but ischemic protection and functional recovery was greater in HG hearts., Conclusions: The data support the adjunctive use of agents that promote glucose uptake during ischemia and suggest that increasing glucose use is more important than decreasing LCAC in the protection against ischemic injury or in the recovery of contractile function.