Comparison of the effect of edoxaban,a direct factor Xa inhibitor,with a direct thrombin inhibitor,melagatran, and heparin on intracerebral hemorrhage induced by collagenase in rats

Introduction

Intracerebral hemorrhage (ICH) is a major clinical concern with anticoagulation therapy. The effect of a new oral direct FXa inhibitor, edoxaban, was determined in a rat model of ICH and compared with a direct thrombin inhibitor, melagatran, and heparin.

Methods

To induce ICH, 0.1 U collagenase type VII was injected into the striatum of male Wistar rats under anesthesia with thiopental or halothane. Immediately after ICH induction, edoxaban, melagatran, or heparin were infused intravenously. Five hours after ICH induction, the brain was removed and ICH size was measured. To estimate the margin of safety, antithrombotic effects were evaluated in a rat venous thrombosis model.

Results

Edoxaban at 6 mg/kg/h significantly increased ICH volume (1.8-fold) and prolonged prothrombin time (PT) 2.8-fold compared to the vehicle group. No deaths were observed with edoxaban. Melagatran at 1 mg/kg/h increased ICH volume at 1 mg/kg/h (2.8-fold) with 6.1-fold PT prolongation. At 3 mg/kg/h, all rats died due to severe ICH (3.9-fold). Heparin at both 100 and 500 U/kg/h significantly increased ICH. At 500 U/kg/h, 5 out of 8 rats died. The doses required for 50% inhibition of thrombosis of edoxaban, melagatran, and heparin were 0.045 mg/kg/h, 0.14 mg/kg/h, and 55 U/kg/h, respectively. The safety margins between antithrombotic and ICH exacerbation effects of these anticoagulants were 133, 7.1, and 1.8, respectively.

Conclusion

The safety margin of edoxaban was wider than that of melagatran or heparin. These results suggest that edoxaban may be preferable from the perspective of ICH exacerbation risk.     

Titanium surface alterations following the use of different mechanical instruments: a systematic review

Objective: To systematically collect and evaluate existing evidence on the effects of different mechanical instruments on the surface characteristics of smooth and rough titanium surfaces. Materials and methods: PubMed‐MEDLINE, Cochrane‐CENTRAL and EMBASE databases were searched up to December 2010 to identify appropriate studies. The eligible studies were controlled studies investigating titanium surface alterations following treatment with different mechanical instruments. Results: In total, 3275 unique papers were identified. A screening of the titles and abstracts resulted in 34 publications that met all of the eligibility criteria. Surface roughness was evaluated using scanning electron microscopy in most studies and using a profilometer in only 10 studies. The rough surfaces evaluated were titanium plasma sprayed and sandblasted and acid‐etched surfaces only. Non‐metal instruments were found to cause minimal or no damage to both smooth and rough titanium surfaces. Metal instruments were found to cause major damage to smooth surfaces. Burs seemed to be the instruments of choice, if smoothening of a rough surface was required. Conclusion: Non‐metal instruments and rubber cups seem to be the instruments of choice for the treatment of smooth surfaces. Similarly, for rough implant surfaces, non‐metal instruments and air abrasives are the instruments of choice, if surface integrity needs to be maintained. Metal instruments and burs are recommended only in cases requiring the smoothening of the surface roughness. The clinical impact of these findings requires clarification.     

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目的比较5种不同方法预备根管后对根尖1／3根管壁的清洁能力。方法将2007年12月至2008年3月在大连市口腔医院颌面外科门诊拔除的60颗离体牙随机分为6组,每组10颗。各组的牙齿先使用Protaper进行根管预备,然后使用不同的方法处理根管壁,分别为：A组H2O2和生理盐水（对照组）、B组EDTA凝胶和5．25％的NACLO,C组超声波荡洗根管、D组Nd：YAG激光、E组超声波（蒸馏水）＋EDTA、F组：超声波（5．25％NAcL0）＋EDTA。完成之后将样本纵向剖开,扫描电镜观察根管壁的界面,比较根尖1／3根管壁的清洁程度和牙本质小管的状态。结果对照组（A组）牙齿根尖部被玷污层全部覆盖,未见开放的牙本质小管;各实验组（B、C、D、E、F组）牙齿根尖部根管壁玷污层不同程度被去除。B、C、D、E、F组根尖1／3玷污层的评分与A组比较,差异有统计学意义（P〈0．05）;5个实验组间根尖1／3玷污层的评分比较,D组与E组差异无统计学意义（P〉0．05）,其余各组间差异均有统计学意义（P〈0．05）。结论5种不同的方法在一定程度上可去除根尖部的玷污层,以超声波（5．25％NACLO）＋EDTA处理根管壁的效果最佳。     

Reversal of slow growth and heartbeat through the restoration of mitochondrial function in clk-1-deficient mouse embryos by exogenous administration of coenzyme Q10

The longevity gene clk-1/coq7 encodes an enzyme that is essential for the biosynthesis of coenzyme Q (CoQ) in mitochondria and regulates the lifespan and behavioral timing in Caenorhabditis elegans and the chronological lifespan in fission yeast. However, whether the mammalian clk-1/coq7 ortholog (clk-1) regulates these phenotypes in mammals remains to be fully evaluated due to the embryonic lethality of clk-1-deficient (clk-1(-/-)) mice. To investigate whether clk-1 regulates biological functions, such as growth and heartbeat, through CoQ in mouse embryos, we cultivated the cells and hearts of clk-1(-/-) mouse embryos at embryonic day 10.5 (E10.5) for at least 10 days in the presence of fetal bovine serum. In embryonic cells, cardiomyocytes, and hearts, the growth and heart rates were significantly slowed in clk-1(-/-) compared with wild-type or heterozygous mouse tissues. Moreover, frequent apoptosis and a significant reduction in mitochondrial functions, including membrane potential and ATP production, were observed in the clk-1(-/-) cells and hearts. The slowed growth and heart rates and the reduced mitochondrial function of clk-1(-/-) embryonic cells and hearts in culture were almost completely rescued by the administration of exogenous CoQ(10). The results indicate that clk-1 regulates growth and heart rates through CoQ-mediated mitochondrial functions in mouse embryos.     

Quantification and characterisation of IgG binding to mould spores by flow cytometry and scanning electron microscopy

The concentration of mould-specific IgG antibodies in serum may objectively indicate mould exposure and can help identifying exposed individuals. Although inhaled spores probably are the most important source of mould exposure, the commonly used methods for detecting mould-specific IgG antibodies are based on extracts from all mould components, with only low contribution from spores. We have developed a flow cytometric method using surface antigens on mould spores for quantifying mould-specific IgG antibodies in serum. Flow cytometric results were evaluated by comparison with ImmunoCap and ELISA measurements. The flow cytometric assay showed a broad linear dose-dependency and correlated moderately to strongly (r=0.41-0.97) with ImmunoCap and ELISA measurements. The IgG antibody binding was studied in detail by immunolabelling in scanning electron microscopy (SEM), revealing that morphology and IgG antibody binding differed among spores, both within and between mould strains. Germination studies by flow cytometry and SEM showed that IgG antibody binding to mould spores was altered during germination due to loss of coat. The present spore based antibody assay are simple and suitable for quantification of mould-specific IgG antibodies in serum, and includes specificity to other and possibly more relevant antigens than existing methods.     

Sustained Release of Minocycline From Minocycline-Calcium-Dextran Sulfate Complex Microparticles for Periodontitis Treatment

It is important to address the periodontitis-associated bacteria in the residual subgingival plaque after scaling and root planing to successfully treat periodontitis. In this study, we explored the possibility of exploiting the ion pairing/complexation of minocycline, Ca²⁺, and sulfate/sulfonate-bearing biopolymers to develop an intrapocket delivery system of minocycline as an adjunct to scaling and root planing. Minocycline-calcium-dextran sulfate complex microparticles were synthesized from minocycline, CaCl₂, and dextran sulfate. They were characterized using Fourier-transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. An in vitro release study was conducted to evaluate the release kinetics of minocycline from these microparticles. Agar disk diffusion assays and biofilm-grown bacteria assays were used to assess antibacterial capability. High loading efficiency (96.98% ± 0.12%) and high loading content (44.69% ± 0.03%) for minocycline were observed for these complex microparticles. Mino-Ca-DS microparticles achieved sustained release of minocycline for at least 9 days at pH 7.4 and 18 days at pH 6.4 in phosphate-buffered saline, respectively. They also demonstrated potent antimicrobial effects against Streptococcus mutans and Aggregatibacter actinomycetemcomitans in agar disk diffusion and biofilm assays. These results suggested that the ion pairing/complexation of minocycline, Ca²⁺, and sulfonate/sulfate-bearing biopolymers can be exploited to develop complex microparticles as local delivery systems for periodontitis treatment.     

Penta-block copolymer microspheres: Impact of polymer characteristics and process parameters on protein release

Here, we aimed to develop protein loaded microspheres (MSs) using penta-block PLGA-based copolymers to obtain sustained and complete protein release. We varied MS morphology and studied the control of protein release. Lysozyme was used as a model protein and MSs were prepared using the solid-in-oil-in-water emulsion solvent extraction method. We synthesized and studied various penta-block PLGA-based copolymers. Copolymer characteristics (LA/GA ratio and molecular weight of PLGA blocks) influenced MS morphology. MS porosity was influenced by process parameters (such as solvent type, polymer concentration, emulsifying speed), whereas the aqueous volume for extraction and stabilizer did not have a significant effect. MSs of the same size, but different morphologies, exhibited different protein release behavior, with porous structures being essential for the continuous and complete release of encapsulated protein. These findings suggest strategies to engineer the morphology of MSs produced from PLGA-based multi-block copolymers to achieve appropriate release rates for a protein delivery system.     

Multimodal imaging for a theranostic approach in a murine model of B-cell lymphoma with engineered nanoparticles

Nanoparticles (NPs) are a promising tool for in vivo multimodality imaging and theranostic applications. Hyaluronic acid (HA)-based NPs have numerous active groups that make them ideal as tumor-targeted carriers. The B-lymphoma neoplastic cells express on their surfaces a clone-specific immunoglobulin receptor (Ig-BCR). The peptide A20-36 (pA20-36) selectively binds to the Ig-BCR of A20 lymphoma cells. In this work, we demonstrated the ability of core-shell chitosan-HA-NPs decorated with pA20-36 to specifically target A20 cells and reduce the tumor burden in a murine xenograft model. We monitored tumor growth using high-frequency ultrasonography and demonstrated targeting specificity and kinetics of the NPs via in vivo fluorescent reflectance imaging. This result was also confirmed by ex vivo magnetic resonance imaging and confocal microscopy. In conclusion, we demonstrated the ability of NPs loaded with fluorescent and paramagnetic tracers to act as multimodal imaging contrast agents and hence as a non-toxic, highly specific theranostic system.     

Soft tissue healing at titanium implants coated with type I collagen. An experimental study in dogs

Objective: To analyse the soft tissue healing at titanium implants coated with type 1 collagen. Material and methods: Six dogs were used. The mandibular pre‐molars and the three anterior maxillary pre‐molars were extracted. Three months later mucoperiosteal flaps were raised and two test and two control implants were installed (3i^® TG Osseotite^®3.75 × 10 and 2.8 mm transmucosal collar). The test implants were coated with a purified porcine type I collagen. Cover screws were placed and flaps were sutured. The sutures were removed 2 weeks later and a plaque‐control programme was initiated. Another 2 weeks later, the procedure was repeated in the contra‐lateral mandibular region. Four weeks after the second implant surgery, biopsies were obtained and prepared for histological examination. Results/Conclusion: The vertical dimensions of the epithelial and connective tissue components as well as the composition of the connective tissue portion facing the implant were similar at collagen‐coated and uncoated implants after 4 and 8 weeks of healing. It is suggested that soft tissue healing to implants coated with type I collagen was similar to that at non‐coated titanium implants and that no adverse reactions to the collagen‐coated implants occurred.