Effect of High-Intensity Rosuvastatin vs. Combination of Low-Intensity Rosuvastatin and Ezetimibe on HbA1c Levels in Patients without Diabetes: A Randomized IDEAL Trial.

There is a dearth of studies investigating whether the combination of low-intensity statins with ezetimibe can reduce the risk of diabetes in patients requiring statin therapy. Therefore, we aimed to evaluate the effects of combination therapy on the prevention of glycated hemoglobin (HbA1c) elevation in patients without diabetes. Sixty-eight patients were randomly assigned in a 1:1 ratio to receive a combination of low-intensity rosuvastatin (5 mg/day) and ezetimibe (10 mg/day) or high-intensity rosuvastatin (20 mg/day). The primary endpoint was the absolute difference in the HbA1c levels at 12 weeks. The HbA1c level showed an overall elevation of 0.11% at 12 weeks compared to that at baseline (mean ± standard deviation: 5.78 ± 0.3%, 95% confidence interval [CI]: 5.86-6.07, p = 0.044). The HbA1c levels did not differ between the groups at 12 weeks (least square mean difference: 0.001, 95% CI: 0.164-0.16, p = 0.999). Our study found that the combination of low-intensity rosuvastatin and ezetimibe did not yield significant differences in HbA1c levels compared to high-intensity rosuvastatin alone after 12 weeks in patients without diabetes. This suggests that the combination of low-intensity rosuvastatin and ezetimibe may not be an effective strategy for preventing HbA1c elevation in patients without diabetes requiring statins.

The DME demethylase regulates sporophyte gene expression, cell proliferation, differentiation, and meristem resurrection.

The flowering plant life cycle consists of alternating haploid (gametophyte) and diploid (sporophyte) generations, where the sporophytic generation begins with fertilization of haploid gametes. In Arabidopsis, genome-wide DNA demethylation is required for normal development, catalyzed by the DEMETER (DME) DNA demethylase in the gamete companion cells of male and female gametophytes. In the sporophyte, postembryonic growth and development are largely dependent on the activity of numerous stem cell niches, or meristems. Analyzing Arabidopsis plants homozygous for a loss-of-function dme-2 allele, we show that DME influences many aspects of sporophytic growth and development. dme-2 mutants exhibited delayed seed germination, variable root hair growth, aberrant cellular proliferation and differentiation followed by enhanced de novo shoot formation, dysregulation of root quiescence and stomatal precursor cells, and inflorescence meristem (IM) resurrection. We also show that sporophytic DME activity exerts a profound effect on the transcriptome of developing Arabidopsis plants, including discrete groups of regulatory genes that are misregulated in dme-2 mutant tissues, allowing us to potentially link phenotypes to changes in specific gene expression pathways. These results show that DME plays a key role in sporophytic development and suggest that DME-mediated active DNA demethylation may be involved in the maintenance of stem cell activities during the sporophytic life cycle in Arabidopsis.

Enhanced cardiac expression of two isoforms of matrix metalloproteinase-2 in experimental diabetes mellitus.

BACKGROUND: Diabetic cardiomyopathy (DM CMP) is defined as cardiomyocyte damage and ventricular dysfunction directly associated with diabetes independent of concomitant coronary artery disease or hypertension. Matrix metalloproteinases (MMPs), especially MMP-2, have been reported to underlie the pathogenesis of DM CMP by increasing extracellular collagen content. PURPOSE: We hypothesized that two discrete MMP-2 isoforms (full length MMP-2, FL-MMP-2; N-terminal truncated MMP-2, NTT-MMP-2) are induced by high glucose stimulation in vitro and in an experimental diabetic heart model. METHODS: Rat cardiomyoblasts (H9C2 cells) were examined to determine whether high glucose can induce the expression of the two isoforms of MMP-2. For the in vivo study, we used the streptozotocin-induced DM mouse heart model and age-matched controls. The changes of each MMP-2 isoform expression in the diabetic mice hearts were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical stains were conducted to identify the location and patterns of MMP-2 isoform expression. Echocardiography was performed to compare and analyze the changes in cardiac function induced by diabetes. RESULTS: Quantitative RT-PCR and immunofluorescence staining showed that the two MMP-2 isoforms were strongly induced by high glucose stimulation in H9C2 cells. Although no definite histologic features of diabetic cardiomyopathy were observed in diabetic mice hearts, left ventricular systolic dysfunction was determined by echocardiography. Quantitative RT-PCR and IHC staining showed this abnormal cardiac function was accompanied with the increases in the mRNA levels of the two isoforms of MMP-2 and related to intracellular localization. CONCLUSION: Two isoforms of MMP-2 were induced by high glucose stimulation in vitro and in a Type 1 DM mouse heart model. Further study is required to examine the role of these isoforms in DM CMP.

White light emission of monolithic InGaN/GaN grown on morphology-controlled, nanostructured GaN templates.

We demonstrated an InGaN/GaN-based, monolithic, white light-emitting diode (LED) without phosphors by using morphology-controlled active layers formed on multi-facet GaN templates containing polar and semipolar surfaces. The nanostructured surface morphology was controlled by changing the growth time, and distinct multiple photoluminescence peaks were observed at 360, 460, and 560 nm; these features were caused by InGaN/GaN-based multiple quantum wells (MQWs) on the nanostructured facets. The origin of each multi-peak was related to the different indium (In) compositions in the different planes of the quantum wells grown on the nanostructured GaN. The emitting units of MQWs in the LED structures were continuously connected, which is different from other GaN-based nanorod or nanowire LEDs. Therefore, the suggested structure had a larger active area. From the electroluminescence spectrum of the fabricated LED, monolithic white light emission with CIE color coordinates of x = 0.306 and y = 0.333 was achieved via multi-facet control combined with morphology control of the metal organic chemical vapor deposition-selective area growth of InGaN/GaN MQWs.

Control of DEMETER DNA demethylase gene transcription in male and female gamete companion cells in Arabidopsis thaliana.

The DEMETER (DME) DNA glycosylase initiates active DNA demethylation via the base-excision repair pathway and is vital for reproduction in Arabidopsis thaliana DME-mediated DNA demethylation is preferentially targeted to small, AT-rich, and nucleosome-depleted euchromatic transposable elements, influencing expression of adjacent genes and leading to imprinting in the endosperm. In the female gametophyte, DME expression and subsequent genome-wide DNA demethylation are confined to the companion cell of the egg, the central cell. Here, we show that, in the male gametophyte, DME expression is limited to the companion cell of sperm, the vegetative cell, and to a narrow window of time: immediately after separation of the companion cell lineage from the germline. We define transcriptional regulatory elements of DME using reporter genes, showing that a small region, which surprisingly lies within the DME gene, controls its expression in male and female companion cells. DME expression from this minimal promoter is sufficient to rescue seed abortion and the aberrant DNA methylome associated with the null dme-2 mutation. Within this minimal promoter, we found short, conserved enhancer sequences necessary for the transcriptional activities of DME and combined predicted binding motifs with published transcription factor binding coordinates to produce a list of candidate upstream pathway members in the genetic circuitry controlling DNA demethylation in gamete companion cells. These data show how DNA demethylation is regulated to facilitate endosperm gene imprinting and potential transgenerational epigenetic regulation, without subjecting the germline to potentially deleterious transposable element demethylation.

DNA demethylation is initiated in the central cells of Arabidopsis and rice.

Cytosine methylation is a DNA modification with important regulatory functions in eukaryotes. In flowering plants, sexual reproduction is accompanied by extensive DNA demethylation, which is required for proper gene expression in the endosperm, a nutritive extraembryonic seed tissue. Endosperm arises from a fusion of a sperm cell carried in the pollen and a female central cell. Endosperm DNA demethylation is observed specifically on the chromosomes inherited from the central cell in Arabidopsis thaliana, rice, and maize, and requires the DEMETER DNA demethylase in Arabidopsis DEMETER is expressed in the central cell before fertilization, suggesting that endosperm demethylation patterns are inherited from the central cell. Down-regulation of the MET1 DNA methyltransferase has also been proposed to contribute to central cell demethylation. However, with the exception of three maize genes, central cell DNA methylation has not been directly measured, leaving the origin and mechanism of endosperm demethylation uncertain. Here, we report genome-wide analysis of DNA methylation in the central cells of Arabidopsis and rice-species that diverged 150 million years ago-as well as in rice egg cells. We find that DNA demethylation in both species is initiated in central cells, which requires DEMETER in Arabidopsis However, we do not observe a global reduction of CG methylation that would be indicative of lowered MET1 activity; on the contrary, CG methylation efficiency is elevated in female gametes compared with nonsexual tissues. Our results demonstrate that locus-specific, active DNA demethylation in the central cell is the origin of maternal chromosome hypomethylation in the endosperm.

Nucleoporin MOS7/Nup88 is required for mitosis in gametogenesis and seed development in Arabidopsis.

Angiosperm reproduction is characterized by alternate diploid sporophytic and haploid gametophytic generations. Gametogenesis shares similarities with that of animals except for the formation of the gametophyte, whereby haploid cells undergo several rounds of postmeiotic mitosis to form gametes and the accessory cells required for successful reproduction. The mechanisms regulating gametophyte development in angiosperms are incompletely understood. Here, we show that the nucleoporin Nup88-homolog MOS7 (Modifier of Snc1,7) plays a crucial role in mitosis during both male and female gametophyte formation in Arabidopsis thaliana. Using a mutagenesis screen, we identify the mos7-5 mutant allele, which causes ovule and pollen abortion in MOS7/mos7-5 heterozygous plants, and preglobular stage embryonic lethality in homozygous mos7-5 seeds. During interphase, we show that MOS7 is localized to the nuclear membrane but, like many nucleoporins, is associated with the spindle apparatus during mitosis. We detect interactions between MOS7 and several nucleoporins known to control spindle dynamics, and find that in pollen from MOS7/mos7-5 heterozygotes, abortion is accompanied by a failure of spindle formation, cell fate specification, and phragmoplast activity. Most intriguingly, we show that following gamete formation by MOS7/mos7-5 heterozygous spores, inheritance of either the MOS7 or the mos7-5 allele by a given gamete does not correlate with its respective survival or abortion. Instead, we suggest a model whereby MOS7, which is highly expressed in the Pollen- and Megaspore Mother Cells, enacts a dosage-limiting effect on the gametes to enable their progression through subsequent mitoses.

Effect on periprocedural myocardial infarction of intra-coronary nicorandil prior to percutaneous coronary intervention in stable and unstable angina.

BACKGROUND: Intravenous nicorandil infusion dilates the coronary artery and reduces inflammation, coronary spasm, and arrhythmia. Periprocedural myocardial infarction (PMI) is a frequent and prognostically important complication of percutaneous coronary intervention (PCI). This prospective randomized study was designed to evaluate the efficacy of intracoronary nicorandil on PMI after elective PCI. METHODS AND RESULTS: Eighty-one patients with stable or unstable angina undergoing PCIs of the left anterior descending artery were randomly assigned to the nicorandil group (n=41) or the control group (n=40). In the nicorandil group, 4 mg of intracoronary nicorandil was infused prior to PCI. Post-PCI, peak levels of creatine kinase (CK)-MB and troponin I were measured and angiographic findings were analyzed. Side branch status was also assessed. All PCIs were successful. One cerebrovascular infarction and one acute ST segment elevation myocardial infarction with acute stent thrombosis occurred in the nicorandil group. No deaths occurred, and no other major cardiac adverse events were observed in either group over 6 months follow-up. The post-PCI peak CK-MB and troponin I levels were not significantly different between the two groups. There were no significant differences between the nicorandil and control subjects in side branch occlusion or flow reduction, or in the jail index. CONCLUSIONS: Intra-coronary nicorandil infusion had no significant effect on PMI and cardiac enzymes after PCI in patients with stable or unstable angina.

Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study.

BACKGROUND: Treatment of critical limb ischemia (CLI) by bypass operation or percutaneous vascular intervention is occasionally difficult. The safety and efficacy of multiple intramuscular adipose tissue-derived mesenchymal stem cells (ATMSC) injections in CLI patients was determined in the study. METHODS AND RESULTS: The study included 15 male CLI patients with ischemic resting pain in 1 limb with/without non-healing ulcers and necrotic foot. ATMSC were isolated from adipose tissue of thromboangiitis obliterans (TAO) patients (B-ATMSC), diabetes patients (D-ATMSC), and healthy donors (control ATMSC). In a colony-forming unit assay, the stromal vascular fraction of TAO and diabetic patients yielded lesser colonies than that of healthy donors. D-ATMSC showed lower proliferation abilitythan B-ATMSC and control ATMSC, but they showed similar angiogenic factor expression with control ATMSC and B-ATMSC. Multiple intramuscular ATMSC injections cause no complications during the follow-up period (mean follow-up time: 6 months). Clinical improvement occurred in 66.7% of patients. Five patients required minor amputation during follow-up, and all amputation sites healed completely. At 6 months, significant improvement was noted on pain rating scales and in claudication walking distance. Digital subtraction angiography before and 6 months after ATMSC implantation showed formation of numerous vascular collateral networks across affected arteries. CONCLUSIONS: Multiple intramuscular ATMSC injections might be a safe alternative to achieve therapeutic angiogenesis in patients with CLI who are refractory to other treatment modalities.

Successful treatment of a ruptured aortic arch aneurysm using a hybrid procedure.

Aortic rupture has a high mortality rate and can be considered a medical emergency. The standard treatment for aortic rupture is surgical repair. An aortic stent graft for a ruptured descending aorta is considered an effective alternative treatment. However, an aortic stent graft is difficult when the aortic aneurysm is in the aortic arch due to supra-aortic vessels. We report on a patient with a ruptured aortic arch aneurysm treated with a hybrid procedure, which involved a carotid to carotid bypass operation and an aortic stent graft. A 71-year-old male patient visited our cardiovascular center suffering from hemoptysis. The chest CT and aortography showed a 9 cm sized aortic arch aneurysm 0.5 cm distal to the left subclavian artery and a hemothorax in the left lung. The patient refused to undergo a full open operation. We performed a carotid to carotid bypass in advance, and two pieces of aortic stent grafts were placed across the left carotid artery and left subclavian artery. The follow up CT showed the aortic stent grafts, no endoleaks and no thrombus in the aortic arch aneurysm. The patient was discharged from the hospital without complication.

Prognosis according to the timing of percutaneous coronary intervention in non-ST segment elevation myocardial infarction, based on the Korean Acute Myocardial Infarction Registry (KAMIR).

BACKGROUND: Patients with acute coronary syndrome without ST-segment elevation (ACS- -NSTE) are at risk for adverse cardiac events. Based on data in the Korean Acute Myocardial Infarction Registry (KAMIR), we analyzed the prognosis according to the timing of percutaneous coronary intervention (PCI) in patients with NSTEMI in Korea. METHODS AND RESULTS: 2,455 patients with NSTEMI in KAMIR were classified according to the time interval from the onset of cardiac symptoms to PCI. Patients in Group I underwent PCI within 24 hours of the onset of symptoms; in Group II between 24 and 48 hours; and in Group III after 48 hours. Major adverse cardiac events (MACEs) are defined as cardiac death, non-cardiac death, myocardial infarction, revascularization and coronary-artery bypass graft surgery. The MACEs were compared between groups. Of the 2,455 patients, 743 (30.2%) were assigned to Group I, 583 (23.7%) to Group II, and 1,129 (45.9%) to Group III. The total incidence of MACEs was higher in Group I than Group III, and similar between Groups I and II (Group I: 15.1%, Group II: 14.4%, Group III: 11.6%, p = 0.053). The incidence of MACEs in the intermediate TIMI risk score group had decreased as the intervention time was delayed. CONCLUSIONS: The prognosis according to the timing of PCI in patients with NSTEMI was similar based on the data in KAMIR. TIMI risk score was related to a high incidence of MACEs.

Function of the DEMETER DNA glycosylase in the Arabidopsis thaliana male gametophyte.

In double fertilization, the vegetative cell of the male gametophyte (pollen) germinates and forms a pollen tube that brings to the female gametophyte two sperm cells that fertilize the egg and central cell to form the embryo and endosperm, respectively. The 5-methylcytosine DNA glycosylase DEMETER (DME), expressed in the central cell, is required for maternal allele demethylation and gene imprinting in the endosperm. By contrast, little is known about the function of DME in the male gametophyte. Here we show that reduced transmission of the paternal mutant dme allele in certain ecotypes reflects, at least in part, defective pollen germination. DME RNA is detected in pollen, but not in isolated sperm cells, suggesting that DME is expressed in the vegetative cell. Bisulfite sequencing experiments show that imprinted genes (MEA and FWA) and a repetitive element (Mu1a) are hypomethylated in the vegetative cell genome compared with the sperm genome, which is a process that requires DME. Moreover, we show that MEA and FWA RNA are detectable in pollen, but not in isolated sperm cells, suggesting that their expression occurs primarily in the vegetative cell. These results suggest that DME is active and demethylates similar genes and transposons in the genomes of the vegetative and central cells in the male and female gametophytes, respectively. Although the genome of the vegetative cell does not participate in double fertilization, its DME-mediated demethylation is important for male fertility and may contribute to the reconfiguration of the methylation landscape that occurs in the vegetative cell genome.

Impact of metabolic syndrome on in-stent restenosis and clinical outcomes after percutaneous coronary stent implantation.

We investigated the impact of metabolic syndrome (MS) on the occurrence of in-stent restenosis (ISR) and long-term major adverse cardiac events (MACEs), including cardiovascular death, myocardial infarction, and target vessel revascularization (TVR) during a follow-up period of 36 months after percutaneous coronary intervention (PCI) with stent implantation in patients with significant preexisting coronary artery disease. MS was not an independent predictor of increased ISR and MACE after PCI.

DNA LIGASE I exerts a maternal effect on seed development in Arabidopsis thaliana.

Maternal effects are defined by mutations that affect the next generation when they are maternally inherited. To date, most indepth studies of maternal effects in plants have attributed their origin to genomic imprinting that restricts expression to the maternal allele. The DNA glycosylase DEMETER (DME) removes methylated cytosine residues, causing transcriptional activation of the maternal allele of imprinted genes. In this study, we show that loss-of-function of the major DNA LIGASE I (AtLIG1) in Arabidopsis thaliana causes maternal effects in the endosperm, which is the seed tissue that nurtures embryo development. AtLIG1 expression is not imprinted and has a limited impact on imprinted gene expression. Genetic interaction analyses further indicate that AtLIG1 acts downstream of DME. The removal of methylated cytosine residues by DME involves the creation of DNA single-strand breaks and our results suggest that AtLIG1 repairs these breaks.

Takayasu's Arteritis Involving the Ostia of Three Large Coronary Arteries.

Takayasu's arteritis can involve the ostia of coronary arteries. We report a patient with Takayasu's arteritis involving the ostia of three large coronary arteries who was successfully treated by percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) and had a good clinical outcome after 12 months. A 37-year-old male with unstable angina was admitted to our cardiovascular center. The patient had Takayasu's arteritis and an aortic valve replacement with a metallic valve due to severe aortic regurgitation 7 years previously. Coronary angiography (CAG) showed a 95% discrete eccentric luminal narrowing at the ostia of the large left anterior descending (LAD) and left circumflex (LCX) arteries, and a 99% discrete eccentric luminal narrowing at the ostium of the large right coronary artery (RCA). The patient was treated with prednisolone for 14 days. Two large paclitaxel-eluting stents (PES) were then implanted in the distal left main coronary artery using the kissing stent technique. After 6 months, a CAG did not reveal restenosis or recurrent coronary artery disease. Thus, PCI with a DES for patients with significant coronary involvement secondary to Takayasu's arteritis is an effective and an alternative treatment when coronary bypass grafting is not option.