The Effect of S-Allyl L-Cysteine on Retinal Ischemia: The Contributions of MCP-1 and PKM2 in the Underlying Medicinal Properties.

Retinal ischemia plays a vital role in vision-threatening retinal ischemic disorders, such as diabetic retinopathy, age-related macular degeneration, glaucoma, etc. The aim of this study was to investigate the effects of S-allyl L-cysteine (SAC) and its associated therapeutic mechanism. Oxidative stress was induced by administration of 500 µM H2O2 for 24 h; SAC demonstrated a dose-dependent neuroprotective effect with significant cell viability effects at 100 µM, and it concurrently downregulated angiogenesis factor PKM2 and inflammatory biomarker MCP-1. In a Wistar rat model of high intraocular pressure (HIOP)-induced retinal ischemia and reperfusion (I/R), post-administration of 100 µM SAC counteracted the ischemic-associated reduction of ERG b-wave amplitude and fluorogold-labeled RGC reduction. This study supports that SAC could protect against retinal ischemia through its anti-oxidative, anti-angiogenic, anti-inflammatory, and neuroprotective properties.

Comparison of Near-Infrared Spectroscopy-Based Cerebral Autoregulatory Indices in Extremely Low Birth Weight Infants.

BACKGROUND: Premature infants are born with immature cerebral autoregulation function and are vulnerable to pressure passive cerebral circulation and subsequent brain injury. Measurements derived from near-infrared spectroscopy (NIRS) have enabled continuous assessment of cerebral vasoreactivity. Although NIRS has enabled a growing field of research, the lack of clear standardization in the field remains problematic. A major limitation of current literature is the absence of a comparative analysis of the different methodologies. OBJECTIVES: To determine the relationship between NIRS-derived continuous indices of cerebral autoregulation in a cohort of extremely low birth weight (ELBW) infants. METHODS: Premature infants of birth weight 401-1000 g were studied during the first 72 h of life. The cerebral oximetry index (COx), hemoglobin volume index (HVx), and tissue oxygenation heart rate reactivity index (TOHRx) were simultaneously calculated. The relationship between each of the indices was assessed with Pearson correlation. RESULTS: Fifty-eight infants with a median gestational age of 25.8 weeks and a median birth weight of 738 g were included. Intraventricular hemorrhage (IVH) was detected in 33% of individuals. COx and HVx demonstrated the highest degree of correlation, although the relationship was moderate at best (r = 0.543, p < 0.001). No correlation was found either between COx and TOHRx (r = 0.318, p < 0.015) or between HVx and TOHRx (r = 0.287, p < 0.029). No significant differences in these relationships were found with respect to IVH and no IVH in subgroup analysis. CONCLUSIONS: COx, HVx, and TOHRx are not numerically equivalent. Caution must be applied when interpreting or comparing results based on different methodologies for measuring cerebral autoregulation. Uniformity regarding data acquisition and analytical methodology are needed to firmly establish a gold standard for neonatal cerebral autoregulation monitoring.

Emodin protected against retinal ischemia insulted neurons through the downregulation of protein overexpression of ß-catenin and vascular endothelium factor.

BACKGROUND: Emodin has been proved to have an anti-ischemic effect on the brain, however little research has been done on its effect on vision-threatening retinal ischemia. Thus, an investigation was carried out into the hypothetical efficacy of emodin against retinal ischemia and the role of ß-catenin/VEGF in its therapeutic mechanism. METHODS: Retinal ischemia, followed by reperfusion (IR), was inducted by raising the intraocular pressure of a Wistar rat's eye to 120 mmHg for 60 min. Additionally, pre-ischemic/post-ischemic intravitreous injections of emodin (4, 10 and 20 µM) or vehicle were carried out on the eye with retinal ischemia. MTT assay, electroretinograms, cresyl violet staining retinal thickness measurements, and fluorogold retrograde labelling of retinal ganglion cells (RGCs) as well as Western blotting were carried out. RESULTS: Cultured RGC-5 cells subjected to oxygen glucose deprivation (OGD) were used to confirm the effective concentrations of emodin (administered 1 h pre-OGD, pre-OGD emodin). The most effective and significant (P = 0.04) dose of pre-OGD emodin was observed at 0.5 µM (cell viability: 47.52 ± 3.99%) as compared to pre-OGD vehicle treatment group (38.30 ± 2.51%). Furthermore, pre-ischemic intravitreous injection of 20 µM emodin (Emo20 + IR = 0.99 ± 0.18, P < 0.001) significantly attenuated the ischemia induced reduction in ERG b-wave amplitude, as compared to pre-ischemic intravitreous vehicle (Vehicle+IR = 0.04 ± 0.02). Post-ischemic intravitreous 20 µM emodin also significantly (P < 0.001) attenuated the ischemia associated b-wave reduction (IR + Em20 = 0.24 ± 0.09). Compared with pre-ischemic intravitreous vehicle (Vehicle+IR; whole retina thickness = 71.80 ± 1.08 µm; inner retina thickness = 20.97 ± 0.85 µm; RGC =2069.12 ± 212.82/0.17mm2), the significant (P < 0.001) protective effect was also present with pre-ischemic administration of emodin. This was shown by observing cresyl violet stained retinal thickness (Emo20 + IR: whole retina = 170.10 ± 0.10 µm; inner retina = 70.65 ± 2.06 µm) and retrograde fluorogold immunolabeled RGC density (4623.53 ± 179.48/0.17mm2). As compared to the normal control (the ratio of ß-catenin/VEGF to ß-actin was set as 1 in the Sham group), the ß-catenin/VEGF protein level significantly (P < 0.001) increased after retinal ischemia and when pre-ischemic intravitreous vehicle (Vehicle+IR = 1.64 ± 0.14/7.67 ± 2.57) was carried out. However, these elevations were significantly (P = 0.02) attenuated by treatment with emodin 20 µM (Emo20 + IR = 1.00 ± 0.19/1.23 ± 0.44). CONCLUSIONS: The present results suggest that emodin might protect against retinal ischemia insulted neurons such as RGCs by significantly downregulating the upregulation of ß-catenin/VEGF protein that occurs during ischemia.

Fortified S-Allyl L-Cysteine: Animal Safety, Effect on Retinal Ischemia, and Role of Wnt in the Underlying Therapeutic Mechanism.

PURPOSE: Retinal ischemia is a medical condition associated with numerous retinal vascular disorders, such as age-related macular degeneration, glaucoma, and diabetic retinopathy. This in vitro cell and in vivo animal study investigated not only the protective effect of S-allyl L-cysteine (SAC, an active component of garlic) against retinal ischemia but also its associated protective mechanisms. METHODS: Retinal ischemia was mimicked by raising the intraocular pressure to 120 mmHg for 1 hour in one eye. The effects of pre-/postischemic administration of vehicle vs. SAC 0.18 mg vs. SAC 0.018 mg vs. SAC 0.0018 mg treatments on retina cells were evaluated through cellular viability (MTT assay), flash electroretinograms (ERGs), and fluorogold retrograde labelling (retinal ganglion cell (RGC) counting). Also, protein immunoblot was utilized to assess the role of Wnt, hypoxia inducible factor (HIF)-1α, and vascular endothelium factor (VEGF) in the proposed anti-ischemic mechanism. Lastly, the safety of drug consumption was investigated for changes in the animal's body weight, ERG waves, and blood biochemical parameters (e.g., glucose levels). RESULTS: The characteristic ischemic changes including significant reduction in ERG b-wave ratio and RGC number were significantly counteracted by pre- and postischemic low dose of SAC. Additionally, ischemia-induced overexpression of Wnt/HIF-1α/VEGF protein was ameliorated significantly by preischemic low dose of SAC. In terms of the animal safety, no significant body weight and electrophysiological differences were observed among defined different concentrations of SAC without following ischemia. In low SAC dosage and vehicle groups, various blood biochemical parameters were normal; however, high and medium concentrations of SAC significantly lowered the levels of uric acid, Hb, and MCHC. CONCLUSION: This study shows that preischemic administration of low SAC dosage has been proved to be safe and most effective against rat retinal ischemia electrophysiologically and/or histopathologically. Moreover, counteracting the ischemia-induced overexpression of Wnt/HIF-1α/VEGF might presently explain SAC's anti-ischemic mechanism.

Effect of Extended-Release Niacin on Carotid Intima Media Thickness, Reactive Hyperemia, and Endothelial Progenitor Cell Mobilization: Insights From the Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) Pilot Trial.

BACKGROUND: Thirty-eight patients with intermediate (30%-60% diameter stenosis) saphenous vein graft lesions were randomized to extended-release niacin (ER-niacin) or placebo for 12 months. We sought to evaluate the impact of ER-niacin on carotid intima media thickness (CIMT), endothelial function, and endothelial progenitor cell (EPC) mobilization. METHODS: Carotid B-mode ultrasound was used to image the common and internal carotid arteries, at baseline and at 12 months after enrollment. Reactive hyperemia peripheral arterial tonometry, as assessed with EndoPAT 2000 (Itamar Medical, Inc) and EPC mobilization assessed with flow cytometry, were measured at enrollment, and at 1 and 12 months. RESULTS: The baseline clinical characteristics were similar in the two study groups. High-density lipoprotein cholesterol levels tended to increase more in the ER-niacin group (5.9 ± 8.7 mg/dL vs 1.4 ± 7.1 mg/dL; P=.14). Between baseline and 12 months, right common carotid artery (0.96 ± 0.44 mm vs 0.70 ± 0.24 mm; P=.04), and left common carotid artery (0.80 ± 0.30 mm vs 0.70 ± 0.20 mm; P=.08) CIMT tended to decrease in the ER-niacin group, compared with no change in the placebo group. The change in logarithmic reactive hyperemia index between 1 month and 12 months was similar in patients receiving ER-niacin vs placebo (0.003 ± 0.12 vs -0.058 ± 0.12; P=.39), whereas EPC mobilization increased in the ER-niacin group and decreased in the placebo group (8.65 ± 28.41 vs -5.87 ± 30.23 EPC colony forming units/mL of peripheral blood; P=.02). CONCLUSIONS: ER-niacin did not have a significant impact on CIMT or endothelial function, but increased EPC mobilization.

Evolution of the American College of Cardiology/American Heart Association Clinical Guidelines.

BACKGROUND: The American College of Cardiology (ACC) and the American Heart Association (AHA) have been developing clinical guidelines to assist practicing clinicians. OBJECTIVES: The goal of this study was to evaluate changes in ACC/AHA guideline recommendations between 2008 and 2014. METHODS: The previous and current ACC/AHA guideline documents that were updated between 2008 and June 2014 were compared to determine changes in Class of Recommendation (COR) and Level of Evidence (LOE). Each recommendation was classified as new, dropped, revised, or unchanged, and the changes in evidence were examined. RESULTS: During the study period, 11 guideline documents (9 disease based and 2 interventional procedure based) were updated. The total number of recommendations decreased from 2,067 to 1,869 (321 fewer recommendations in disease-based guidelines and 123 additional recommendations in interventional procedure-based guidelines). The recommendation class distribution of the updated guidelines was 50.1% Class I (previously 50.8%), 39.4% Class II (previously 35.4%), and 10.4% Class III (previously 13.8%) (p = 0.001). The LOE distribution among updated versions was 15.0% for LOE: A (previously 13.3%), 50.8% for LOE: B (previously 41.4%), and 34.2% for LOE C (previously 45.3%) (p < 0.001). Among all guidelines, 859 recommendations were new, 1,339 were dropped, 881 were unchanged in COR and LOE, and 129 were revised. Of the revised guidelines, 75 recommendations had an increase in LOE (the majority from LOE: C to LOE: B); 34 recommendations had a decrease in LOE; and 20 recommendations had class changes. LOE increases were justified by introduction of new randomized controlled trials, new studies, and new meta-analyses. CONCLUSIONS: The ACC/AHA guideline recommendations are undergoing significant changes, becoming more evidence based and scientifically robust with a tendency to exclude recommendations with insufficient scientific evidence.