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Adsorption and diffusion of isolated water molecules such as monomers and dimers on Pt(1 1 1) surface were directly observed by the scanning tunneling microscopy (STM) at very low coverage and at low temperature. A water dimer appears as a 6-fold symmetric “flower-like” protrusion, which can be explained based on the model that a hydrogen bond acceptor molecule in the dimer is rotating around a donor molecule. We obtained vibrational spectrum of individual water dimers by means of single-molecule vibrational spectroscopic method from the vibrationally-induced lateral hopping motions. Analyzing the spectra suggests a detailed model for adsorption structure of a water dimer where an acceptor molecule of the dimer points toward the surface to form O–H–Pt hydrogen bonding.

The adsorption of individual acetylene molecules at a Pd(1 1 1) surface has been studied with scanning tunneling microscopy (STM) at 4.7 K. The adsorbed acetylene molecules appear in the STM images as a combination of a protrusion and a pair of depressions. To determine the adsorption site and configuration of the molecule, we performed rotational manipulation of the molecule by injecting tunneling electrons into the molecule as well as performing atomically resolved STM imaging. The STM images revealed that the molecules have a total of six equivalent adsorption orientations on Pd(1 1 1), indicating three equivalent rotational states on two (both fcc and hcp) 3-fold hollow adsorption sites. From the atomically resolved STM images of the surface with a monatomic step edge, we have distinguished the two types of 3-fold hollow sites and confirmed that the fcc site is more stable than the hcp site at a low temperature.

Study design Case report. Objective To describe an intraoperative complication occurring from abdominal aortic penetration during a vertebroplasty procedure for vertebral fractures on Th12 and L1. Summary of background data A vertebroplasty is a minimally invasive and widely performed procedure in elderly and high-risk patients, although there is a risk of life-threatening complications including aortic injury. However, little is known about the treatment of iatrogenic aortic penetration occurring during a vertebroplasty. Methods An 80-year-old female underwent a scheduled vertebroplasty procedure. When the needle was advanced into the L1 vertebral body, arterial blood spurted out from the needle hub and fluoroscopic imaging revealed penetration of the aorta. To minimize bleeding, we depressed blood pressure and kept the needle in place. While vital signs were maintained, we prepared for blood transfusion and circulation monitoring and consulted a cardiothoracic surgeon and a cardiologist. Contrast medium injected via the needle revealed that a hematoma had formed to shift the aortic wall beyond the needle. Circulation was stable while pressure of the needle decreased, thus the hematoma was thought to have become coagulated and the needle was cautiously withdrawn. Results After placing the patient in a supine position, aortic angiography revealed no leakage around the aorta and she was transferred to the intensive care unit. On postoperative day 1, no leakage around the aorta was confirmed on computed tomographic scans and the patient was extubated. During the 2-year follow-up period, no arterial complication was observed. Conclusion Conservative treatment is optional for accidental aortic penetration during a vertebroplasty when a tamponade effect is expected. In cases with circulatory collapse, when the tamponade effect seems insufficient or a free wall rupture is suspected, prompt removal of the needle and surgical repair should be considered. Level of evidence 5.

The fundamental structure of an isolated water dimer on Pt(111) was determined by means of a spectroscopic method using scanning tunneling microscopy (STM) and density functional theory (DFT) calculations. Two water molecules on adjacent atop sites form a dimer through a hydrogen bond, and they rotate even at a substrate temperature of 5 K. Action spectroscopy using STM (STM-AS) for water dimer hopping allows us to obtain the vibrational spectrum of a single water dimer on Pt(111). Comparisons between the experiments and theory show that one of the OH groups of the acceptor water molecule points toward the surface to form an −OH···Pt hydrogen bond.

The purpose of this prospective study was to evaluate the effects ofone-lung ventilation on the activity of the cardiac autonomic nervous system.Ten adult patients who underwent thoracotomy were endotracheally intubatedwith a double-lumen tube under general anesthesia using isoflurane. Afterinduction of anesthesia, a continuous, 256-sec electrocardiogram (ECG) wasobtained during bilateral lung ventilation (control) followed by recordingsduring one-lung ventilation of each side. Using the R–R intervaltachograms obtained for the 256-sec ECGs, low frequency (LF: 0.04–0.15Hz) and high frequency (HF: 0.15–0.40 Hz) bands of the spectral densityof the heart rate variability and the HF/LF ratio were analyzed using the fastFourier transform algorithm. Log(HF), which indicates parasympatheticactivity, increased during one-lung ventilation on each side, but did notdiffer between ventilated sides. Log(LF), which represents sympathetic andparasympathetic activity, increased similarly to log(HF) on both sides.Log(HF/LF), the balance of the sympathetic and parasympathetic activity, didnot change during one-lung ventilation. We suggest that one-lung ventilationalone does not substantially affect the cardiac autonomic nervous system.

We compared the antithrombotic properties of a factor Xa inhibitor (DX-9065a) with those of a thrombin inhibitor (melagatran) in a rat disseminated intravascular coagulation model and a rat venous thrombosis model. Rat disseminated intravascular coagulation and venous thrombosis models were produced by injection of tissue factor and platinum wire placement, respectively. DX-9065a exerted antithrombotic effects dose dependently in both models. Melagatran was also effective in the venous thrombosis model, whereas it showed an aggravation in the disseminated intravascular coagulation model at low but not high doses. In the in vitro study, DX-9065a decreased the C max of the thrombin generation curve in plasma irrespective of whether protein C was present or not. However, melagatran increased the C max at low concentrations when protein C was present. This increase was not detected in protein C-deficient plasma. These results suggest that, unlike DX-9065a, melagatran in low doses aggravates disseminated intravascular coagulation by increasing thrombin generation, which may be partly due to suppression of negative feedback by activated protein C.

To test the hypothesis that elderly patients who have surgery for femoral neck fractures may have delirium not only after surgery but before surgery, we prospectively investigated the perioperative temporal profile of cognitive function in such patients. We performed the Abbreviated Mental Test (AMT) six times in each patient (on the day of admission, 3 days after admission, on the day before surgery, 2 days after surgery, 7 days after surgery, and on the day of discharge). Patients were given no premedication and were anesthetized with spinal anesthesia using 0.2% hypobaric tetracaine. Of the 68 patients who were admitted because of a diagnosis of fractured neck of the femur and were scheduled to have surgery, 27 patients were subjected to analysis. Four and three patients showed a significant decrease (3 or more points) in AMT score 2 and 7 days after surgery, respectively. We conclude that surgery may have a stronger impact on cognitive function than environmental change shortly after admission in elderly patients with femoral neck fractures. (J Geriatr Psychiatry Neurol 2000; 13:206-209).

In a pitch conversion method and device which can reduce data throughput while suppressing a degradation of sound quality due to a pitch conversion as much as possible, an input signal pitch pattern per predetermined processing unit and a target pitch pattern are inputted, and a degradation degree indicating how a waveform of the input signal degrades upon pitch conversion from the input signal pitch pattern to the target pitch pattern is calculated. Alternatively, a degradation degree corresponding to a voice state and a phonemic type of the input signal is extracted from a database in which all of combinations of voice states and phonemic types estimated are associated with the degradation degrees to be recorded. Then, a pitch converter which performs a pitch conversion with small data throughput and a pitch converter which performs a pitch conversion with large data throughput are switched over depending on the degradation degree.

Antithrombin (AT) is a major physiological inhibitor of coagulation factors, primarily inhibiting thrombin and factor Xa (FXa). Binding of heparin and its related pentasaccharides, fondaparinux, to AT dramatically accelerates inhibition of thrombin and FXa. Entire AT-dependency of heparins may result in decreased anticoagulant effects in patients with inherited or acquired AT deficiencies. Objectives: We have developed an orally active direct (i.e. AT-independent) FXa inhibitor, DU-176b. The objectives of this study were to examine the anticoagulant and antithrombotic effects of DU-176b, fondaparinux, and heparin in heterozygous AT deficient (AT+/−) mice (Refs 1, 2), and to determine the impact of AT deficiency on the efficacies of these anticoagulants. Methods: [In vitro study] Plasma obtained from wild type (AT+/+, C57BL/6J) and AT+/− mice were subjected to measurement of levels of AT antigen and activity. The anticoagulant effects on prothrombin time (PT) and activated partial thromboplastin time (APTT) was measured and the drug concentrations were calculated required to double the clotting time (CT2). [In vivo study] Male AT+/+ and AT+/− mice were fasted over night. Thrombosis was induced in the inferior vena cava by applying filter paper (1 x 5 mm) presoaked in 15% FeCl3 for 10 min. Thrombus was removed 60 min after FeCl3 treatment and its protein content was assessed by Bradford method. DU-176b was orally administered 60 min before, fondaparinux was given s.c. 30 min before, and heparin was injected into the jugular vein 3 min before thrombus induction. Relative potencies of antithrombotic effects in AT+/− mice to those in AT+/+ mice were analyzed by parallel line assay. Results: [In vitro study] Plasma levels of AT antigen and activity in AT+/− mice were deceased to 40% compared with AT+/+ plasma. PT-CT2 of DU-176b was 0.72 μM in AT+/+ plasma and 0.74 μM in AT+/− plasma, respectively, indicating that anticoagulant activity of the direct FXa inhibitor was not affected by heterozygous AT deficiency. APTT-CT2 of fondaparinux and heparin in AT+/+ plasma was 3.8 μM and 14 mU/mL, respectively, whereas APTT-CT2 in AT+/− plasma was 9.2 μM and 20 mU/mL, respectively. Therefore, anticoagulant activities of such AT-dependent inhibitors were attenuated in AT+/− plasma. [In vivo study] All three anticoagulants inhibited venous thrombus formation of AT+/+ mice in dose-dependent manners. In AT+/− mice, the antithrombotic effects of fondaparinux and heparin were less potent than those in AT+/+ mice. In contrast, DU-176b prevented thrombus formation equipotently in both mice. Relative potencies of DU-176b, fondaparinux and heparin were 0.84, 0.40, and 0.70, respectively. Conclusion: DU-176b exerts a comparable antithrombotic effect even in individuals with low plasma AT antigens and activities. Thus, DU-176b may be prioritized over AT-dependent agents for use at the fixed dose in patients with lower plasma AT concentrations.

DU-176b is a novel potent, orally active and selective direct inhibitor of factor Xa (FXa). Direct FXa inhibitors have been reported to exert little effect on bleeding time at antithrombotic doses in animal studies. The aim of the present study was to compare the antithrombotic and hemorrhagic effects of DU-176b with unfractionated heparin (UFH), low molecular weight heparin (LMWH; dalteparin) and warfarin in rat models of thrombosis and hemorrhage. Rats were treated with DU-176b, UFH and LMWH by continuous intravenous infusion for 2 – 2.5 h, and with warfarin orally once daily for 4 days before thrombosis or hemorrhage. Thrombosis was induced by the insertion of a platinum wire into the inferior vena cava and left for 60 min. Tail template bleeding time was measured after an incision on the tail. DU-176b dose-dependently inhibited thrombus formation in the venous thrombosis model. The dose required for 50% inhibition (ED50) was 0.076 mg/kg/h. In contrast, the dose of DU-176b to double template bleeding time (BT2) was 0.75 mg/kg/h, indicating 10-fold dissociation of the doses of antithrombotic and hemorrhagic effects. UFH, LMWH and warfarin also prevented thrombus formation (ED50 = 56 U/kg/h, 66 U/kg/h and 0.16 mg/kg/day, respectively), but prolonged bleeding time at slightly higher doses (BT2 = 73 U/kg/h, 135 U/kg/h and 0.21 mg/kg/day, respectively) than the effective doses. The dissociation of the doses for these compounds was only 1.3, 2.0 and 1.3-fold, respectively. Moreover, the slope of dose-antithrombotic response curve of DU-176b was significantly slighter than those of UFH, LMWH and warfarin, indicating that the therapeutic dose range of DU-176b would be wider than those of the other anticoagulants. These results suggest that direct and selective inhibition of FXa by DU-176b is preferable for the treatment of thrombotic diseases in the aspect of lack of compromising primary hemostasis.

Factor Xa (FXa) is an attractive target for the treatment of thrombosis due to its crucial role in the blood coagulation cascade. Fondaparinux, a selective FXa inhibitor, has been approved for clinical use to prevent deep vein thrombosis after orthopedic surgery; however, it requires antithrombin (AT) to exert its antithrombotic effect. It is reported that AT dependent anticoagulants such as heparin are less effective to suppress platelet-rich arterial-type thrombus due to its inaccessibility to thrombus-bound FXa/thrombin. We have developed a potent direct (i.e. AT independent) FXa inhibitor, DU-176b. The objective of this study is to compare the antithrombotic properties of a direct selective FXa inhibitor, DU-176b, with an AT dependent selective FXa inhibitor, fondaparinux. We evaluated the antithrombotic effects of DU-176b and fondaparinux in rat models of arterial and venous thrombosis. The arterial and venous thrombosis was induced by topical application of ferric chloride to the carotid artery and by insertion of a platinum wire into the inferior vena cava, respectively. DU-176b (0.05 – 1.25 mg/kg/h) and fondaparinux (1 – 10 mg/kg/h for arterial thrombosis and 0.03 – 1 mg/kg/h for venous thrombosis) were intravenously administered as continuous infusions. DU-176b prevented both arterial and venous thrombosis in the same dose range. In contrast, the effective doses of fondaparinux markedly differed between these models. A higher dose of fondaparinux more than 100 times was required to inhibit arterial thrombosis compared with venous thrombosis. These results suggest that direct inhibition of FXa is a preferable strategy to AT dependent inhibition for the prevention of thrombus formation in the arteries.

Factor Xa (FXa) is a key serine protease in the coagulation cascade and is a promising target enzyme for developing a new antithrombotic agent. Our first clinical candidate for a small molecular direct FXa inhibitor DX-9065a potently inhibits FXa (Ki = 41 nM) and exerts antithrombotic effects in animal models. However, due to its poor bioavailability (10% in monkeys) the compound is used only as an injectable formulation in clinical studies. Here we report in vitro characteristics of serine proteases inhibition, anticoagulant effects and in vivo antithrombotic efficacy of DU-176b, a novel, potent and orally active direct FXa inhibitor. DU-176b competitively inhibited human FXa with a Ki value of 0.561 nM, indicating 70-fold increase in FXa inhibitory activity compared with DX-9065a. DU-176b demonstrated 10,000-fold selectivity relative to inhibition of thrombin (Ki = 6.00 μM), and had no effects on the enzymatic activities of factor VIIa, t-PA, plasmin, trypsin and chymotrypsin. In human plasma, DU-176b prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) in a concentration-dependent manner. Its concentrations for doubling these clotting times were 0.256 and 0.508 μM, respectively. After oral administration of DU-176b to rats, significant anti-Xa activity was observed in plasma over 4 h. The oral bioavailability of DU-176b (approximately 50%) was significantly higher than that of DX-9065a (10%) in monkeys. The antithrombotic efficacy of DU-176b was examined by oral administration to rats 30 minutes prior to thrombogenic stimuli. In a venous stasis thrombosis model, DU-176b (0.5 – 12.5 mg/kg, p.o.) dose-dependently inhibited thrombus formation, prolonged PT, and revealed plasma anti-Xa activity. DU-176b also exerted significant anticoagulant effect in a rat model of tissue factor-induced disseminated intravascular coagulation at doses of 0.1 – 2.5 mg/kg, p.o. These results demonstrate that DU-176b is a potent and selective factor Xa inhibitor that possesses antithrombotic effect after oral administration. DU-176b has the potential to be clinically useful for prophylaxis and treatment of several thrombotic diseases.