Reducing contact resistance of MoS2-based field effect transistors through uniform interlayer insertion via atomic layer deposition.

Molybdenum disulfide (MoS2), a semiconducting two-dimensional layered transition metal dichalcogenide (2D TMDC), with attractive properties enables the opening of a new electronics era beyond Si. However, the notoriously high contact resistance (RC) regardless of the electrode metal has been a major challenge in the practical applications of MoS2-based electronics. Moreover, it is difficult to lower RC because the conventional doping technique is unsuitable for MoS2 due to its ultrathin nature. Therefore, the metal-insulator-semiconductor (MIS) architecture has been proposed as a method to fabricate a reliable and stable contact with low RC. Herein, we introduce a strategy to fabricate MIS contact based on atomic layer deposition (ALD) to dramatically reduce the RC of single-layer MoS2 field effect transistors (FETs). We utilize ALD Al2O3 as an interlayer for the MIS contact of bottom-gated MoS2 FETs. Based on the Langmuir isotherm, the uniformity of ALD Al2O3 films on MoS2 can be increased by modulating the precursor injection pressures even at low temperatures of 150 °C. We discovered, for the first time, that film uniformity critically affects RC without altering the film thickness. Additionally, we can add functionality to the uniform interlayer by adopting isopropyl alcohol (IPA) as an oxidant. Tunneling resistance across the MIS contact is lowered by n-type doping of MoS2 induced by IPA as the oxidant in the ALD process. Through a highly uniform interlayer combined with strong doping, the contact resistance is improved by more than two orders of magnitude compared to that of other MoS2 FETs fabricated in this study.

Independent and incremental prognostic value of exercise stress echocardiography in low cardiovascular risk female patients with chest pain.

BACKGROUND: Exercise stress echocardiography (ESEcho) is sufficiently sensitive and has high enough specificity for the clinical detection of coronary artery disease (CAD) in women. However, there was little data about the ability of ESEcho to detect CAD and predict clinical outcomes in female patients with chest pain and low global cardiovascular (CV) risks. The purposes of this study were (1) to determine the diagnostic accuracy of ESEcho, (2) to evaluate the clinical outcomes of major cardiovascular outcome (MACE), and (3) to assess the incremental prognostic value of ESEcho for the prediction of MACE in Korean female patients with low CV risks. METHODS: Over a period of 15 years, 3396 patients (57±10 years) female patients with chest pain but no previous history of CAD undergoing ESEcho and exercise stress electrocardiography (ESECG) were assessed. RESULTS: During a median follow-up period of 4.8 years (2.8-6.2 years), there were 19 (0.61%) MACE. Positive results for ESEcho were seen in 134 patients (3.9%). The sensitivity and specificity of ESEcho were 66.7% and 84.8%, respectively. Positive ESEcho was an independent predictor of MACE (multivariate hazard ratio: 0.019, 95% CI: 0.004-0.081). ESEcho was incremental to clinical and ESECG parameters to predict the MACE in low CV risk women. CONCLUSIONS: ESEcho is effective for the diagnosis of CAD in Korean female patients with chest pain, a population characterized by low cardiovascular risk profiles. Positive ESEcho was an independent predictor of MACE, and negative results were associated with favorable clinical outcomes. ESEcho was incremental to clinical and ESECG parameters to predict the MACE in low CV risk women.

Investigation on Contact Properties of 2D van der Waals Semimetallic 1T-TiS2/MoS2 Heterojunctions.

Two-dimensional transition metal dichalcogenides (2D TMDCs) are considered promising alternatives to Si as channel materials because of the possibility of retaining their superior electronic transport properties even at atomic body thicknesses. However, the realization of high-performance 2D TMDC field-effect transistors remains a challenge owing to Fermi-level pinning (FLP) caused by gap states and the inherent high Schottky barrier height (SBH) within the metal contact and channel layer. This study demonstrates that high-quality van der Waals (vdW) heterojunction-based contacts can be formed by depositing semimetallic TiS2 onto monolayer (ML) MoS2. After confirming the successful formation of a TiS2/ML MoS2 heterojunction, the contact properties of vdW semimetal TiS2 were thoroughly investigated. With clean interfaces of the TiS2/ML MoS2 heterojunctions, atomic-layer-deposited TiS2 can induce gap-state saturation and suppress FLP. Consequently, compared with conventional evaporated metal electrodes, the TiS2/ML MoS2 heterojunctions exhibit a lower SBH of 8.54 meV and better contact properties. This, in turn, substantially improves the overall performance of the device, including its on-current, subthreshold swing, and threshold voltage. Furthermore, we believe that our proposed strategy for vdW-based contact formation will contribute to the development of 2D materials used in next-generation electronics.

Trans-radial versus trans-femoral intervention for the treatment of coronary bifurcations: results from Coronary Bifurcation Stenting Registry.

Trans-radial (TR) approach is increasingly recognized as an alternative to the routine use of trans-femoral (TF) approach. However, there are limited data comparing the outcomes of these two approaches for the treatment of coronary bifurcation lesions. We evaluated outcomes of TR and TF percutaneous coronary interventions (PCI) in this complex lesion. Procedural outcomes and clinical events were compared in 1,668 patients who underwent PCI for non-left main bifurcation lesions, according to the vascular approach, either TR (n = 503) or TF (n = 1,165). The primary outcome was major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR) in all patients and in 424 propensity-score matched pairs of patients. There were no significant differences between TR and TF approaches for procedural success in the main vessel (99.6% vs 98.6%, P = 0.08) and side branches (62.6% vs 66.7%, P = 0.11). Over a mean follow-up of 22 months, cardiac death or MI (1.8% vs 2.2%, P = 0.45), TLR (4.0% vs 5.2%, P = 0.22), and MACE (5.2% vs 7.0%, P = 0.11) did not significantly differ between TR and TF groups, respectively. These results were consistent after propensity score-matched analysis. In conclusion, TR PCI is a feasible alternative approach to conventional TF approaches for bifurcation PCI (clinicaltrials.gov number: NCT00851526).

Atomic-Layer-Deposition-Based 2D Transition Metal Chalcogenides: Synthesis, Modulation, and Applications.

Transition metal chalcogenides (TMCs) are a large family of 2D materials with different properties, and are promising candidates for a wide range of applications such as nanoelectronics, sensors, energy conversion, and energy storage. In the research of new materials, the development and investigation of industry-compatible synthesis techniques is of key importance. In this respect, it is important to study 2D TMC materials synthesized by the atomic layer deposition (ALD) technique, which is widely applied in industries. In addition to the synthesis of 2D TMCs, ALD is used to modulate the characteristic of 2D TMCs such as their carrier density and morphology. So far, the improvement of thin film uniformity without oxidation and the synthesis of low-dimensional nanomaterials on 2D TMCs have been the research focus. Herein, the synthesis and modulation of 2D TMCs by ALD is described, and the characteristics of ALD-based TMCs used in nanoelectronics, sensors, and energy applications are discussed.

Procoagulant and prothrombotic activation of human erythrocytes by phosphatidic acid.

Increased phosphatidic acid (PA) and phospholipase D (PLD) activity are frequently observed in various disease states including cancers, diabetes, sepsis, and thrombosis. Previously, PA has been regarded as just a precursor for lysophosphatidic acid (LPA) and diacylglycerol (DAG). However, increasing evidence has suggested independent biological activities of PA itself. In the present study, we demonstrated that PA can enhance thrombogenic activities in human erythrocytes through phosphatidylserine (PS) exposure in a Ca(2+)-dependent manner. In freshly isolated human erythrocytes, treatment of PA or PLD induced PS exposure. PA-induced PS exposure was not attenuated by inhibitors of phospholipase A(2) or phosphatidate phosphatase, which converts PA to LPA or DAG. An intracellular Ca(2+) increase and the resultant activation of Ca(2+)-dependent PKC-alpha appeared to underlie the PA-induced PS exposure through the activation of scramblase. A marginal decrease in flippase activity was also noted, contributing further to the maintenance of exposed PS on the outer membrane. PA-treated erythrocytes showed strong thrombogenic activities, as demonstrated by increased thrombin generation, endothelial cell adhesion, and erythrocyte aggregation. Importantly, these procoagulant activations by PA were confirmed in a rat in vivo venous thrombosis model, where PA significantly enhanced thrombus formation. In conclusion, these results suggest that PA can induce thrombogenic activities in erythrocytes through PS exposure, which can increase thrombus formation and ultimately contribute to the development of cardiovascular diseases.

A naphthoquinone derivative can induce anemia through phosphatidylserine exposure-mediated erythrophagocytosis.

A naphthoquinone derivative, beta-lapachone (betaL; 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione), is receiving huge attention for its potent therapeutic effects against various diseases. However, during the preclinical safety evaluation, repeated oral treatment of betaL in rats induced anemia, i.e., a significantly decreased erythrocyte count. In this study, in an effort to elucidate the mechanism underlying the betaL-induced anemia, we investigated the effects of betaL on erythrocytes with freshly isolated human erythrocytes in vitro and rat in vivo. betaL did not induce erythrocyte hemolysis, indicating that direct hemotoxicity was not involved in betaL-associated anemia. Meanwhile, phosphatidylserine (PS) exposure along with spherocytic shape change and microvesicle generation, important factors in the facilitation of erythrophagocytosis, were increased significantly by betaL. The PS exposure on erythrocytes was from betaL-induced reactive oxygen species generation and subsequent depletion of reduced glutathione and protein thiol, which culminated in the modified activities of phospholipid translocases, i.e., inhibition of flippase and activation of scramblase. It is important to note that coincubation of macrophage with betaL-treated erythrocyte in vitro showed increased erythrophagocytosis, demonstrating that the removal of erythrocyte by macrophage can be facilitated by betaL-induced PS exposure. In good accordance with these in vitro results, after oral administration of betaL in rats, increased PS exposure and depletion of glutathione were observed along with enhanced splenic sequestration of erythrocytes. In conclusion, these results suggest that betaL-induced anemia might be mediated through the PS exposure and subsequent erythrophagocytosis, providing novel insight into the drug-induced anemia.

Trivalent methylated arsenical-induced phosphatidylserine exposure and apoptosis in platelets may lead to increased thrombus formation.

Trivalent methylated metabolites of arsenic, monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), have been found highly reactive and toxic in various cells and in vivo animal models, suggesting their roles in the arsenic-associated toxicity. However, their effects on cardiovascular system including blood cells, one of the most important targets for arsenic toxicity, remain poorly understood. Here we found that MMA(III) and DMA(III) could induce procoagulant activity and apoptosis in platelets, which play key roles in the development of various cardiovascular diseases (CVDs) through excessive thrombus formation. In freshly isolated human platelets, treatment of MMA(III) resulted in phosphatidylserine (PS) exposure, a hallmark of procoagulant activation, accompanied by distinctive apoptotic features including mitochondrial membrane potential disruption, cytochrome c release, and caspase-3 activation. These procoagulant activation and apoptotic features were found to be mediated by the depletion of protein thiol and intracellular ATP, and flippase inhibition by MMA(III), while the intracellular calcium increase or reactive oxygen species generation was not involved. Importantly, increased platelet procoagulant activity by MMA(III) resulted in enhanced blood coagulation and excessive thrombus formation in a rat in vivo venous thrombosis model. DMA(III) also induced PS-exposure with apoptotic features mediated by protein thiol depletion, which resulted in enhanced thrombin generation. In summary, we believe that this study provides an important evidence for the role of trivalent methylated arsenic metabolites in arsenic-associated CVDs, giving a novel insight into the role of platelet apoptosis in toxicant-induced cardiovascular toxicity.

Inhibition of platelet aggregation by 1-methyl-4-phenyl pyridinium ion (MPP+) through ATP depletion: Evidence for the reduced platelet activities in Parkinson's disease.

Neuronal accumulation of 1-methyl-4-phenylpyridinium ion (MPP(+)), the metabolite of neural toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP), induces a rapid depletion of cellular ATP level and loss of neuronal cell viability which simulates human Parkinson's disease (PD). Since ATP plays an important role in the physiology and function of platelets, which share many biochemical and physiological features with neuronal cells, we examined the effect of MPP(+) on platelet aggregation and viability using freshly isolated rat platelets. While the treatment of MPP(+) to platelets did not induce cytotoxicity, it significantly attenuated agonist-induced platelet aggregation in a concentration dependent manner. The inhibition of aggregation by MPP(+) was mediated by the depletion of the cytoplasmic ATP pool and resultant decreased ATP secretion. Different from the previous reports in neuronal cells, MPP(+) did not affect intracellular levels of glutathione and cytoplasmic Ca(2+) in platelets. The combined treatment with MPP(+) and 2-deoxyglucose, a glycolysis inhibitor, showed the additive effect in the decrease of ATP secretion and intracellular content. Consistent with these findings, inhibitory effects of MPP(+) on platelet aggregation was significantly enhanced by the treatment with 2-deoxyglucose. In conclusion, these results suggested that MPP(+) can induce ATP depletion in platelets and attenuate platelet aggregation providing a new theory on the reduced platelet activities in PD patients.

Salsolinol, an endogenous neurotoxin, enhances platelet aggregation and thrombus formation.

Salsolinol, an endogenous neurotoxin, is known to be involved in the neuropathy of Parkinson's disease and chronic alcoholism. In these diseases, increased thrombotic events are also commonly reported, yet the mechanism underlying remains poorly understood. Here we report that salsolinol can enhance agonist-induced platelet aggregation and granular secretion, which is essential in the thrombus formation. In rat and human platelets, agonist-induced platelet aggregation was significantly increased by salsolinol in a concentration-dependent manner. Agonist-induced granular secretions of serotonin and concomitant P-selectin expression were also augmented by salsolinol. alpha2-adrenergic blockers attenuated the salsolinol-enhanced aggregation and the inhibition of cyclic AMP generation was found, suggesting the involvement of alpha2-adrenergic receptor-mediated pathways in these events. In accord with the in-vitro results, in an arterial and venous thrombosis model in vivo in the rat, salsolinol shortened vessel occlusion time and increased thrombus formation, respectively. In conclusion, we demonstrated that salsolinol can enhance agonist-induced aggregation and granular secretion in platelets through alpha2-adrenergic receptor activation, which resulted in the increased thrombus formation in vivo. These results suggest that salsolinol-enhanced platelet aggregation could be a possible contributing factor to the thrombotic events observed in Parkinson's disease and alcoholism.

Lysophosphatidic acid induces thrombogenic activity through phosphatidylserine exposure and procoagulant microvesicle generation in human erythrocytes.

OBJECTIVE: Although erythrocytes have been suggested to play a role in blood clotting, mediated through phosphatidylserine (PS) exposure and/or PS-bearing microvesicle generation, an endogenous substance that triggers the membrane alterations leading to a procoagulant activity in erythrocytes has not been reported. We now demonstrated that lysophosphatidic acid (LPA), an important lipid mediator in various pathophysiological processes, induces PS exposure and procoagulant microvesicle generation in erythrocytes, which represent a biological significance resulting in induction of thrombogenic activity. METHODS AND RESULTS: In human erythrocytes, LPA treatment resulted in PS exposure on remnant cells and PS-bearing microvesicle generation in a concentration-dependent manner. Consistent with the microvesicle generation, scanning electron microscopic study revealed that LPA treatment induced surface changes, alteration of normal discocytic shape into echinocytes followed by spherocytes. Surprisingly, chelation of intracellular calcium did not affect LPA-induced PS exposure and microvesicle generation. On the other hand, protein kinase C (PKC) inhibitors significantly reduced PS exposure and microvesicle generation induced by LPA, reflecting the role of calcium-independent PKC. Activation of PKC was confirmed by Western blot analysis showing translocation of calcium-independent isoform, PKCzeta, to erythrocyte membrane. The activity of flippase, which is important in the maintenance of membrane asymmetry, was also inhibited by LPA. Furthermore, LPA-exposed erythrocytes actually potentiated the thrombin generation as determined by prothrombinase assay and accelerated the coagulation process initiated by recombinant human tissue factor in plasma. The adherence of erythrocytes to endothelial cells, another important feature of thrombogenic process, was also stimulated by LPA treatment. CONCLUSIONS: These results suggested that LPA-exposed erythrocytes could make an important contribution to thrombosis mediated through PS exposure and procoagulant microvesicle generation.

Co-oxidation-mediated xenobiotic activation and cytotoxicity by 12-lipoxygenase in intact platelets.

Peroxidase-mediated co-oxidation process has been suggested as a major alternative pathway for xenobiotic bioactivation other than hepatic cytochrome P450 monooxygenase system. Despite the wealth of reports on the possible involvement of co-oxidation in bioactivation of various compounds, clear manifestation of co-oxidation-mediated xenobiotic bioactivation in intact cell system without extra sources of peroxidase system has been difficult to demonstrate, mainly due to the natural scarcity of peroxidase activities in fresh intact cells. In the present study, arachidonic acid (AA) dependent bioactivation of alpha-naphthol, a representative phenolic compound, was demonstrated as shown by covalent binding increases in alpha-naphthol concentration dependent manner in freshly prepared intact platelets, where two AA dependent representative peroxidases, 12-lipoxygenase (12-LOX) and prostaglandin H synthase (PHS) are abundantly expressed. Inhibitors of 12-LOX attenuated the covalent binding of alpha-naphthol while inhibitors of PHS were not effective, indicating the predominant role of 12-LOX in AA-initiated co-oxidation in intact platelets. In addition, free radical scavengers and thiol donors prevented effectively the bioactivation of alpha-naphthol, suggesting the involvement of naphthoxy radical or naphthoxy-derived radical generation. Notably, the co-oxidation process resulted in enhanced cytotoxicities of alpha-naphthol against platelets indeed, as observed by cellular membrane disturbance and mitochondrial membrane potential decrease. With these results, we believe that an important in vitro evidence of peroxidase-mediated xenobiotic activation was provided for understanding the toxicological implication of peroxidase-mediated co-oxidation in the xenobiotic bioactivation.

Vascular smooth muscle dysfunction induced by monomethylarsonous acid (MMA III): a contributing factor to arsenic-associated cardiovascular diseases.

While arsenic in drinking water is known to cause various cardiovascular diseases in human, exact mechanism still remains elusive. Recently, trivalent-methylated arsenicals, the metabolites of inorganic arsenic, were shown to have higher cytotoxic potential than inorganic arsenic. To study the role of these metabolites in arsenic-induced cardiovascular diseases, we investigated the effect of monomethylarsonous acid (MMA III), a major trivalent-methylated arsenical, on vasomotor tone of blood vessels. In isolated rat thoracic aorta and small mesenteric arteries, MMA III irreversibly suppressed normal vasoconstriction induced by three distinct agonists of phenylephrine (PE), serotonin and endothelin-1. Inhibition of vasoconstriction was retained in aortic rings without endothelium, suggesting that MMA III directly impaired the contractile function of vascular smooth muscle. The effect of MMA III was mediated by inhibition of PE-induced Ca2+ increase as found in confocal microscopy and fluorimeter in-lined organ chamber technique. The attenuation of Ca2+ increase was from concomitant inhibition of release from intracellular store and extracellular Ca2+ influx via L-type Ca2+ channel, which was blocked by MMA III as shown in voltage-clamp assay in Xenopus oocytes. MMA III did not affect downstream process of Ca2+, as shown in permeabilized arterial strips. In in vivo rat model, MMA III attenuated PE-induced blood pressure increase indeed, supporting the clinical relevance of these in vitro findings. In conclusion, MMA III-induced smooth muscle dysfunction through disturbance of Ca2+ regulation, which results in impaired vasoconstriction and aberrant blood pressure change. This study will provide a new insight into the role of trivalent-methylated arsenicals in arsenic-associated cardiovascular diseases.

The roles of ATP and calcium in morphological changes and cytotoxicity induced by 1,4-benzoquinone in platelets.

To understand the mechanism of 1,4-benzoquinone-induced cytotoxicity in platelets, the roles of ATP and calcium in platelet toxicity and morphological changes were investigated. Using scanning electron microscopy, morphological changes including membrane blebbing were observed in rat platelets 5 min after exposure to 1,4-benzoquinone, which were significantly different from shape changes (pseudopod formation) observed in response to physiological agonists. Benzoquinone-induced membrane blebbing of platelets was associated with rapid depletion of intracellular ATP and was independent of the presence of extracellular calcium. Benzoquinone-induced platelet lysis observed between 20 and 30 min was dependent on extracellular calcium and associated with increased cytosolic calcium. Cytotoxicity induced by 1,4-benzoquinone was inhibited by antagonists of calmodulin, suggesting that calmodulin could play an important role in platelet toxicity. These results suggested that the progression of events for benzoquinone-induced cytotoxicity in platelets was as follows: 1,4-benzoquinone depletes intracellular ATP; membrane blebbing occurs; calcium homeostasis is disrupted, activation of calmodulin-dependent processes results; finally cytotoxicity occurs.

Inorganic arsenite potentiates vasoconstriction through calcium sensitization in vascular smooth muscle.

Chronic exposure to arsenic is well known as the cause of cardiovascular diseases such as hypertension. To investigate the effect of arsenic on blood vessels, we examined whether arsenic affected the contraction of aortic rings in an isolated organ bath system. Treatment with arsenite, a trivalent inorganic species, increased vasoconstriction induced by phenylephrine or serotonin in a concentration-dependent manner. Among the arsenic species tested--arsenite, pentavalent inorganic species (arsenate), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV)--arsenite was the most potent. Similar effects were also observed in aortic rings without endothelium, suggesting that vascular smooth muscle plays a key role in enhancing vasoconstriction induced by arsenite. This hypercontraction by arsenite was well correlated with the extent of myosin light chain (MLC) phosphorylation stimulated by phenylephrine. Direct Ca2+ measurement using fura-2 dye in aortic strips revealed that arsenite enhanced vasoconstriction induced by high K+ without concomitant increase in intracellular Ca2+ elevation, suggesting that, rather than direct Ca2+ elevation, Ca2+ sensitization may be a major contributor to the enhanced vasoconstriction by arsenite. Consistent with these in vitro results, 2-hr pretreatment of 1.0 mg/kg intravenous arsenite augmented phenylephrine-induced blood pressure increase in conscious rats. All these results suggest that arsenite increases agonist-induced vasoconstriction mediated by MLC phosphorylation in smooth muscles and that calcium sensitization is one of the key mechanisms for the hypercontraction induced by arsenite in blood vessels.

Generation of free radical by interaction of iron with thiols in human plasma and its possible significance.

It has been reported that iron can generate reactive oxygen species (ROS) with thiols. In this study, we examined the interaction of iron with thiols in plasma and the generation of ROS. In human plasma, unlike with Fe(3+), treatment with Fe(2+) increased lucigenin-enhanced chemiluminescence in a concentration-dependent manner, and this was inhibited by superoxide dismutase. Boiling of plasma did not affect chemiluminescence generation induced by Fe(2+). Thiol depletion in plasma by pretreatment with N-ethylmaleimide (NEM) decreased chemiluminescence significantly. Consistent with these findings, albumin, the major thiol contributor in plasma, also generated ROS with Fe(2+). Treatment with Fe(2+) resulted in significant reduction of oxygen radical absorbance capacity (ORAC value) in plasma followed by an increase in low-density lipoprotein (LDL) oxidation. These results suggest that generation of ROS by nonenzymatic reaction of Fe(2+) with plasma thiols could lead to reduction of total antioxidant capacity in plasma, thereby enhancing susceptibility of plasma LDL to oxidation under iron overload conditions.

Aggravation of hepatopulmonary syndrome after sildenafil treatment in a patient with coexisting portopulmonary hypertension.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. Their pathophysiological mechanisms clearly differ. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation. In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling, but is rarely associated with hypoxia. We report a case of a patient who had both HPS and PPHTN at the time of presentation. HPS was aggravated after sildenafil administration for the treatment of PPHTN. We demonstrated increased amount of intrapulmonay shunt after sildenafil challenge by using agitated saline contrast transthoracic echocardiography.

Transradial versus transfemoral intervention for the treatment of left main coronary bifurcations: results from the COBIS (COronary BIfurcation Stenting) II Registry.

OBJECTIVES: We compared clinical outcomes of transradial (TR) and transfemoral (TF) percutaneous coronary interventions (PCI) in patients with left main coronary artery (LMCA) bifurcation lesions. BACKGROUND: The use of TR approach is growing as an alternative to the routine use of the TF approach. However, there are limited data comparing the outcomes of these two approaches for the treatment of LMCA bifurcation lesions. METHODS: Between January 2003 and December 2009, a total of 853 patients undergoing PCI using drug-eluting stent (DES) implantation for LMCA bifurcation lesions were enrolled from 18 centers in Korea. We classified patients into the TR group (n = 212) and TF group (n = 641) according to the vascular approach. The primary outcome was major adverse cardiac event (MACE) rate, including composite of cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR) in all patients and in 483 propensity-score matched patients. RESULTS: There were no significant differences between TR and TF approaches for procedural success in the main vessel (98.6% vs. 99.7%; P=.07) and side branches (90.6% vs. 94.4%; P=.05). Thrombolysis in Myocardial Infarction major or minor bleeding occurred less frequently in the TR group than in the TF group (2.4% vs. 9.4%; P=.01). Over a median follow-up of 35 months, MACE rate did not significantly differ between TR and TF groups (9.9% vs. 14.5%; adjusted hazard ratio, 0.80; 95% confidence interval, 0.49-1.29; P=.36). These results were consistent after propensity-score matched analysis. CONCLUSIONS: TR-PCI is a safe and effective vascular approach, even in patients with LMCA bifurcation lesions undergoing PCI with DES implantation.

Antithrombotic activity of LB30057, a newly synthesized direct thrombin inhibitor.

An amidrazonophenylalanine derivative, LB30057, inhibits the catalytic activity of thrombin potently by interaction with the active site of thrombin, and has high water solubility. In the present study, we evaluated the effect of LB30057 on the biological activities of thrombin at various tissues, and determined whether thrombin inhibition by LB30057 could reduce the incidence of occlusive thrombosis in an in vivo animal model. Treatment with LB30057 to human plasma prolonged clotting times in a concentration-dependent manner. LB30057 suppressed significantly thrombin-induced phosphatidylserine (PS) exposure in platelets, suggesting that LB30057 could inhibit blood coagulation accelerated by PS exposure. In human platelets, soluble thrombin- and clot-induced platelet aggregation was inhibited by LB30057 potently. Consistent with this finding, LB30057 showed concentration-dependent inhibitory effects on serotonin secretion and P-selectin expression induced by thrombin in platelets. In the blood vessel isolated from the guinea pig, treatment with LB30057 resulted in a concentration-dependent inhibition of thrombin-induced vascular contraction. In vivo study revealed that LB30057 following oral administration significantly increased the time to occlusion and improved carotid arterial patency using rat carotid artery thrombosis model. All these results suggest that LB30057 is a potent inhibitor of biological activities of thrombin at various target tissues and, therefore, might be developed as an antithrombotic agent for treatment and prevention of thrombotic diseases.

Arsenic-induced dysfunction in relaxation of blood vessels.

Several epidemiological studies have suggested that exposure to arsenic is strongly correlated with the development of cardiovascular diseases such as hypertension. To determine whether arsenic affects vasomotor tone in blood vessels, we investigated the effect of arsenic on vasorelaxation using isolated rat aortic rings in an organ-bath system. Treatment with arsenite inhibited acetylcholine-induced relaxation of the aortic rings in a concentration-dependent manner, whereas several other arsenic species did not have any effect. Consistent with these findings, the levels of guanosine 3',5'-cyclic monophosphate (cGMP) in the aortic rings were significantly reduced by arsenite treatment. In cultured human aortic endothelial cells, treatment with arsenite resulted in a concentration-dependent inhibition of endothelial nitric oxide synthase (eNOS). In addition, higher concentrations of arsenite decreased the relaxation induced by sodium nitroprusside (an NO donor) and 8-Br-cGMP (a cGMP analog) in aortic rings without endothelium. These in vitro results indicate that arsenite is capable of suppressing relaxation in blood vessels by inhibiting eNOS activity in endothelial cells and by impairing the relaxation machinery in smooth muscle cells. In vivo studies revealed that the reduction of blood pressure by acetylcholine infusion was significantly suppressed after arsenite was administered intravenously to rats. These data suggest that an impairment of vasomotor tone due to arsenite exposure may be a contributing factor in the development of cardiovascular disease.