Effect of individual proton pump inhibitors on cardiovascular events in patients treated with clopidogrel following coronary stenting:: Results From the Ibaraki Cardiac Assessment Study Registry

Objectives : The aim of this study was to evaluate whether combination therapy of clopidogrel and proton pump inhibitors (PPIs) causes higher numbers of cardiovascular events than clopidogrel alone in Japanese patients. Background : PPIs are often prescribed in combination with clopidogrel following coronary stenting. PPIs are reported to diminish the effect of clopidogrel because both are metabolized by CYP2C19. However, no reports address the effects of PPIs on cardiovascular events following coronary stenting in the Japanese population. Methods : A total of 1,887 patients treated with clopidogrel following coronary stenting were enrolled in the Ibaraki Cardiac Assessment Study (ICAS) registry. All subjects were classified into two groups according to treatment without (n = 819) or with (n = 1,068) PPI. Propensity score analysis matched 1:1 according to treatment without PPI (n = 500) or with PPI (n = 500). Primary endpoint was the composite of all‐cause death or myocardial infarction. Results : No significant difference was observed in the primary endpoint between the group without PPI and the group with PPI (4.6% vs. 4.6%, P = 0.77). In contrast, a significant difference was found between the group without PPI and with PPI in regard to the incidence of gastrointestinal bleeding at the end of the follow‐up period and the specific PPI prescribed (2.4% vs. 0.8%, adjusted HR = 0.30, 95% Confidence interval 0.08‐0.87, P = 0.026) after propensity score matching. Conclusions : No significant association between PPI use and primary endpoint was observed in the Japanese population, whereas PPI use resulted in a significant reduction in the rate of gastrointestinal bleeding. © 2012 Wiley Periodicals, Inc.     

Synthesis of Pd–Ru solid-solution nanoparticles by pulsed plasma in liquid method

We have synthesized solid-solution nanoparticles (Pd : Ru = 1 : 3, 1 : 1 and 3 : 1) in an immiscible Pd–Ru system by the pulsed plasma in liquid method using Pd–Ru mixture bulk electrodes. The particle sizes of the floated and sedimented samples were measured to be <10 and <20 nm, respectively, via high-resolution transmission electron microscopy (HR-TEM). The lattice parameters of nanoparticles followed the Vegard''s law, and the energy-dispersive X-ray spectroscopy (EDX) results almost coincided with those obtained for the starting bulk mixtures. The solid-solution structures and local structure were confirmed via HR-TEM, X-ray photoelectron spectroscopy (XPS) and X-ray absorption fine structure spectroscopy (XAFS).

We have synthesized solid-solution nanoparticles (Pd : Ru = 1 : 3, 1 : 1 and 3 : 1) in an immiscible Pd–Ru system by the pulsed plasma in liquid method using Pd–Ru mixture bulk electrodes.     

Continuous syntheses of carbon-supported Pd and Pd@Pt core–shell nanoparticles using a flow-type single-mode microwave reactor

Continuous syntheses of carbon-supported Pd@Pt core–shell nanoparticles were performed using microwave-assisted flow reaction in polyol to synthesize carbon-supported core Pd with subsequent direct coating of a Pt shell. By optimizing the amount of NaOH, almost all Pt precursors contributed to shell formation without specific chemicals.

Continuous syntheses of carbon-supported Pd@Pt core–shell nanoparticles were performed using flow processes including microwave-assisted Pd core–nanoparticle formation.

Continuous flow syntheses have attracted attention as a powerful method for organic, nanomaterial, and pharmaceutical syntheses because of various features that produce benefits in terms of efficiency, safety, and reduction of environmental burdens.^1–7 Advances of homogeneous heating and mixing techniques in continuous flow reactors have engendered further developments for precise reaction control, which is expected to create innovative materials through combination with multiple-step flow syntheses.Microwave (MW) dielectric heating has been recognized as a promising methodology for continuous flow syntheses because rapid or selective heating raises the reaction rate and product yield.^8–18 For the last two decades, most MW apparatus has been batch-type equipped with a stirring mechanism in a multi-mode cavity. Therefore, conventionally used MW-assisted flow reactors have been mainly of the modified batch-type. Results show that the electromagnetic field distribution can be spatially disordered, causing inhomogeneous heating of the reactor.^19–25 Improvements of reactors suitable for flow-type work have been studied actively in recent years to improve their energy efficiency and to make irradiation of MW more homogeneous.^26–37We originally designed a MW flow reactor system that forms a homogeneous heating zone through generation of a uniform electromagnetic field in a cylindrical single-mode MW cavity.^26,30 The temperatures of flowing liquids in the reactor were controlled precisely via the resonance frequency auto-tracking function. Continuous flow syntheses of metal nanoparticle, metal-oxide, and binary metal core–shell systems with uniform particle size have been achieved using our MW reactor system.^26,38,39 Furthermore, large-scale production necessary for industrial applications can be achieved through integration of multiple MW reactors.³⁰Carbon-supported metal catalysts are widely used in various chemical transformations and fine organic syntheses. Particularly, binary metal systems such as Pd@Pt core–shell nanoparticles have attracted considerable interest for electro-catalysis in polymer electrolyte membrane fuel cells (PEMFC) because of their enhanced oxygen reduction activity compared to a single-use Pt catalyst. Binary metal systems also contribute to minimization of the usage of valuable Pt.^40–51 Earlier studies of carbon-supported Pd@Pt syntheses involved multiple steps of batch procedures such as separation, washing and pre-treatment of core metal nanoparticles, coating procedures of metal shells, and dispersion onto carbon supports. Flow-through processes generally present advantages over batch processes in terms of simplicity and high efficiency in continuous material production.We present here a continuous synthesis of carbon-supported Pd and Pd@Pt core–shell nanoparticles as a synthesis example of a carbon-supported metal catalyst using our MW flow reactor. This system incorporates the direct transfer of a core metal dispersion into a shell formation reaction without isolation. Nanoparticle desorption is prevented by nanoparticle synthesis directly on a carbon support. The presence of protective agents that are commonly used in nanoparticle syntheses, such as poly(N-vinylpyrrolidone), can limit the chemical activity of the catalyst. Nevertheless, this system requires no protective agent. Moreover, this system is a simple polyol synthesis that uses no strong reducing agent. It therefore imposes little or no environmental burden. For this study, the particle size and distribution of metals in Pd and Pd@Pt core–shell nanoparticles were characterized using TEM, HAADF-STEM observations, and EDS elemental mapping. From electrochemical measurements, the catalytic performance of Pd@Pt core–shell nanoparticles was evaluated.A schematic view of the process for the continuous synthesis of carbon-supported Pd@Pt core–shell nanoparticles is presented in Fig. 1. Details of single-mode MW flow reactor are described in ESI.^† We attempted to conduct a series of reactions coherently in a flow reaction system, i.e., MW-assisted flow reaction for the synthesis of carbon supported core Pd nanoparticles with subsequent deposition of the Pt shell. Typically, a mixture containing Na₂[PdCl₄] (1–4 mM) in ethylene glycol (EG), carbon support (Vulcan XC72, 0.1 wt%), and an aqueous NaOH solution were prepared. This mixture was introduced continuously into the PTFE tube reactor placed in the center of the MW cavity. Here, EG works as the reaction solvent as well as the reducing agent that converts Pd(ii) into Pd(0) nanoparticles. The MW heating temperature was set to 100 °C with the flow rate of 80 ml h^−l, which corresponds to residence time of 4 s. The carbon-supported Pd nanoparticles were transferred directly to the Pt shell formation process without particle isolation. The dispersed solution was introduced into a T-type mixer and was mixed with a EG solution of H₂[PtCl₆]·6H₂O (10 mM). The molar ratio of Pd : Pt was fixed to 1 : 1. Subsequently, after additional aqueous NaOH solution was mixed at the second T-mixer, the reaction mixture was taken out of the mixer and was let to stand at room temperature (1–72 h) for Pt shell growth.Open in a separate windowFig. 1Schematic showing continuous synthesis of carbon-supported Pd and Pd@Pt core–shell nanoparticles. The Pd nanoparticles were dispersed on the carbon support by MW heating of the EG solution. The solution was then transferred directly to Pt shell formation.Rapid formation of Pd nanoparticles with average size of 3.0 nm took place at the carbon-support surface during MW heating in the tubular reactor (Fig. 2a). Most of the Pd(ii) precursor was converted instantaneously to Pd(0) nanoparticles and was well dispersed over the carbon surface. Fig. 2b shows the time profile of the outlet temperature and applied MW power during continuous synthesis of carbon-supported Pd nanoparticles. The solution temperature rose instantaneously, reaching the setting temperature in a few seconds. This temperature was maintained with high precision (±2 °C) by the continuous supply of ca. 18 W microwave power. No appreciable deposition of metal was observed inside of the PTFE tube. It is noteworthy that Pd of 98% or more was supported on carbon by heating for 4 s at 100 °C from ICP-OES measurement. Our earlier report described continuous polyol (EG) synthesis of Pd nanoparticles as nearly completed with 6 s at 200 °C.³⁹ The reaction temperature in polyol synthesis containing the carbon was considerably low, suggesting that selective reduction reaction occurs on the carbon surface, which is a high electron donating property.Open in a separate windowFig. 2(a) TEM image of carbon-supported Pd nanoparticles synthesized using the MW flow reactor. The average particle size was 3.0 nm. (b) The time profile of the temperature at the reactor outlet and applied microwave power during continuous synthesis of carbon-supported Pd nanoparticles. Na₂[PdCl₄] = 2 mM, NaOH = 10 mM.The concentrations of Na₂[PdCl₄] precursor and NaOH affect the Pd nanoparticle size. Results show that the Pd particle size increased as the initial concentration of Na₂[PdCl₄] increased (Fig. S1a and b^†). Change of NaOH concentration exerted a stronger influence on the particle size. Nanoparticles of 12.3 nm were observed without addition of NaOH, whereas 2.6 nm size particles were deposited at the concentration of 20 mM (Fig. S1c and d^†). The higher NaOH concentration led to instantaneous nucleation and rapid completion of reduction. The Pd nanoparticle surface is equilibrated with Pd–O⁻ and Pd–OH depending on the NaOH concentration. The surface is more negative at high concentrations of NaOH because of the increase of the number of Pd–O⁻, which inhibits the mutual aggregation and further particle growth. Furthermore, to control the Pd nanoparticle morphology, we conducted synthesis by adding NaBr, which has been reported as effective for cubic Pd nanoparticle synthesis.⁵² However, because reduction of the Pd precursor derives from electron donation from both the polyol and the carbon support, morphological control was not achieved (Fig. S2^†). That finding suggests that morphological control is difficult to achieve by adding surfactant agents to the polyol.For Pt shell formation, carbon supported Pd nanoparticles (3.0 nm average particle size) were mixed with H₂[PtCl₆]·6H₂O solution with the molar ratio of Pd : Pt = 1 : 1. Then additional NaOH solution was mixed. As described in earlier reports,³⁹ alkaline conditions under which base hydrolysis and reduction of [PtCl₆]²⁻ to [Pt(OH)₄]²⁻ takes place are necessary for effective Pt shell formation. It is noteworthy that the added Pt precursor was almost entirely supported on carbon within 24 h in cases where an appropriate amount of additional NaOH (5 mM) was mixed by the second T-mixer (Fig. 3a). However, for 10 mM, nucleation and growth of single Pt nanoparticles were enhanced in place of core–shell formation. Consequently, a mixture of Pd@Pt and single Pt nanoparticles was formed on the carbon support (Fig. 3b). Very fine Pt nanoparticles were observed in the supernatant solution.Open in a separate windowFig. 3(a) Time profiles of residual ratio of Pt in the mixed solutions. Horizontal axis was left standing time. Carbon-support in the mixed solution after added the Pt precursor was precipitated by centrifugation. The supernatant solution was measured by ICP-OES. Concentrations of additional NaOH were 0, 5, and 10 mM. (b) TEM image of carbon-supported Pd@Pt core–shell nanoparticles. The synthesis conditions of Pd nanoparticles were Na₂[PdCl₄] (2 mM) and NaOH (10 mM). The molar ratio of Na₂[PdCl₄] : H₂[PtCl₆]·6H₂O was 1 : 1, and additional NaOH concentration was 10 mM. After left standing for 72 h, the mixture of Pd@Pt and single Pt nanoparticles (1–2 nm) was formed on carbon-support. Fig. 4a portrays a TEM image of carbon supported Pd@Pt core–shell nanoparticles. The average particle size of Pd@Pt core–shell nanoparticles was 3.6 nm after being left to stand for 24 h: larger than the initial Pd nanoparticles (3.0 nm). Fig. 4b shows the HAADF-STEM image of Pd@Pt core–shell nanoparticles supported on carbon. The core–shell structure of the particles can be ascertained from the contrast of the image. The Z-contrast image shows the presence of brighter shells over darker cores. Actually, the contrast is strongly dependent on the atomic number (Z) of the element.⁵³ The Z values of Pt (Z = 78) and Pd (Z = 46) differ considerably. Therefore, the image shows the formation of Pd@Pt core–shell structure with the uniform elemental distribution. Elemental mapping images by STEM-EDS show that both Pd and Pt metals were present in all the observed nanoparticles (Fig. 4c). Based on the atomic ratio (Pd : Pt = 49 : 51), they show good agreement with the designed values. The Pt shell thickness was estimated as about 0.6 nm, which corresponds to 2–3 atomic layer thickness of Pt encapsulating the Pd core metal, indicating good agreement with Fig. 4b image. For an earlier study, uniform Pt shells were formed by dropwise injection of the Pt precursor solution because the Pt shell growth rate differs depending on the crystal plane of the Pd nanoparticle.⁴⁶ For more precise control of shell thickness in our system, the Pt precursor solution should be mixed in multiple steps.Open in a separate windowFig. 4(a) TEM image and (b) HAADF-STEM image of carbon-supported Pd@Pt core–shell nanoparticles and the line profile of contrast. (c) Elemental mapping image of carbon-supported Pd@Pt core–shell nanoparticles, where Pd and Pt elements are displayed respectively as red and green. The EDS atomic ratio of Pd : Pt was 49 : 51. The synthesis conditions of Pd nanoparticles were Na₂[PdCl₄] (2 mM) and NaOH (10 mM). The molar ratio of Na₂[PdCl₄] : H₂[PtCl₆]·6H₂O was 1 : 1. The concentration of additional NaOH were 5 mM. It was left standing for 24 h.A comparison of the catalytic performance of the carbon-supported Pd@Pt core–shell and Pt nanoparticles is shown in Fig. S3.^† For this experiment, carbon-supported Pt nanoparticles with Pt 2 mM were prepared as a reference catalyst using a similar synthetic method. The initial Pt mass activities of the carbon-supported Pd@Pt and Pt nanoparticles were, respectively, 0.39 and 0.24 A mg_Pt⁻¹, improving by the core–shell structure. In addition, durability tests for carbon-supported Pd@Pt nanoparticles show that the reduction rate of Pt mass activity after 5000 cycles was only 2%. The catalytic activities of carbon-supported Pd@Pt nanoparticles were superior in terms of durability, suggesting that the Pt shell was firmly formed.     

Clinical significance of and future perspectives for hepatic arterial infusion chemotherapy in patients with liver metastases from colorectal cancer

The most common site of metastases in patients with colorectal cancer is the liver. Hepatic resection is considered to be the treatment of choice for liver metastasis from colorectal cancer; however, hepatic resection can be performed in only 20 or 25 % of all patients. Recurrence develops in the remnant liver or other organs after hepatic resection in over half of all patients with liver-only metastasis. Hepatic arterial infusion (HAI) chemotherapy can provide relatively high concentrations of drugs to microscopic or macroscopic metastases in the liver, with less toxicity than systemic administration. Meta-analyses have shown HAI chemotherapy to have a significantly higher response rate than systemic chemotherapy and its effect on extrahepatic metastases is negligible. HAI chemotherapy provides much better local control of liver metastases from colorectal cancer than systemic chemotherapy. However, well-controlled studies are needed to elucidate the optimal treatment strategies for neoadjuvant and postoperative adjuvant chemotherapy that optimally combine HAI chemotherapy, molecular targeted agents, and systemic chemotherapy such as FOLFOX or FOLFIRI.     

Intrahepatic biliary ablation with pure ethanol: an experimental model of biliary atresia

Purpose

We describe a new rat model of biliary atresia, induced by biliary ablation with pure ethanol.

Methods

A catheter was inserted and fixed in the common bile duct of male rats. Saline or pure ethanol was injected through the catheter and the animals were monitored for 8 weeks thereafter. We measured total bilirubin (T-Bil), aspartate aminotransferase (AST), alanine transaminase (ALT), and hyaluronic acid (HA) and examined liver biopsy specimens immunohistochemically for α-smooth muscle actin staining (α-SMA) and transforming growth factor-β1 (TGF-β1).

Results

The ethanol injection group animals were further divided into a temporary and a persistent liver dysfunction group. In the persistent group, T-Bil, AST, ALT and HA levels were significantly higher after 8 weeks in the persistent group than in the control group and the temporary group. In the ethanol injection group, α-SMA expression was prominent in the surrounding proliferative bile ducts and portal areas. The distribution of TGF-β1 was found prominently in hepatocytes in the center of nodules and in ductular epithelial cells.

Conclusions

This study characterizes the effects of ethanol-induced bile duct injury in rats, resulting in sclerosing cholangitis and its secondary effects. We believe that this experimental model will prove useful in the study of biliary atresia.     

Usefulness of perflubutane microbubble-enhanced ultrasound in imaging and detection of prostate cancer: phase II multicenter clinical trial

Purpose

To explore the possibility of targeted biopsy (TBx) using transrectal ultrasound (US) with perflubutane microbubbles, we studied the findings of different cancerous tissue imaging modalities and evaluated needle biopsy in prostate cancer (PCa) using contrast-enhanced US (CEUS) in a multicenter clinical trial.

Methods

Seventy-one patients undergoing prostate biopsy received intravenous injection of perflubutane microbubbles (Sonazoid^®). We evaluated and compared images obtained by CEUS. The safety observation period was 2 days after contrast administration.

Results

Among the 30 patients with cancer, one or more sites with findings suggestive of cancer in CEUS were detected in 23 patients (32.4%) by TBx. Although 22 patients had positive cores of cancer by systematic biopsy (SBx), 8 patients had positive cores of cancer in TBx alone (11.3%). There was a significant difference in cancer detection rate by TBx between two cohorts with PSA < 10 ng/mL (22.9%) and PSA ≥ 10 ng/mL (52.2%) (P < 0.02). Close observation of various CEUS findings with Sonazoid^® enabled targeting of cancerous areas, and consequently, a significant difference (P < 0.05) in the detection rate of cancer was recognized in the transition zone (TZ): SBx; 21/120 (17.5%) and TBx; 17/55 (30.9%). The incidence of adverse events was 6.7% and that of adverse reactions was 4%.

Conclusions

CEUS with Sonazoid^® improved the detection rate of PCa by visualizing cancerous lesions. More detailed examination of CEUS images provided efficient characterization especially in the TZ area. TBx according to this procedure is expected to enable a lower number of biopsies and more accurate diagnosis of PCa.