Phenethyl Isothiocyanate Protects against High Fat/Cholesterol Diet-Induced Obesity and Atherosclerosis in C57BL/6 Mice

This study concerns obesity-related atherosclerosis, hyperlipidemia, and chronic inflammation. We studied the anti-obesity and anti-atherosclerosis effects of phenethyl isothiocyanate (PEITC) and explored their underlying mechanisms. We established an animal model of high fat/cholesterol-induced obesity in C57BL/6 mice fed for 13 weeks. We divided the mice into five groups: control (CON), high fat/cholesterol (HFCD), HFCD with 3 mg/kg/day gallic acid (HFCD + G), and HFCD with PEITC (30 and 75 mg/kg/day; HFCD + P30 and P75). The body weight, total cholesterol, and triglyceride were significantly lower in the HFCD + P75 group than in the HFCD group. Hepatic lipid accumulation and atherosclerotic plaque formation in the aorta were significantly lower in both HFCD + PEITC groups than in the HFCD group, as revealed by hematoxylin and eosin (H&E) staining. To elucidate the mechanism, we identified the expression of genes related to inflammation, reverse cholesterol transport, and lipid accumulation pathway in the liver. The expression levels of peroxisome proliferator activated receptor gamma (PPARγ), liver-X-receptor α (LXR-α), and ATP binding cassette subfamily A member 1 (ABCA1) were increased, while those of scavenger receptor A (SR-A1), cluster of differentiation 36 (CD36), and nuclear factor-kappa B (NF-κB) were decreased in the HFCD + P75 group compared with those in the HFCD group. Moreover, PEITC modulated H3K9 and H3K27 acetylation, H3K4 dimethylation, and H3K27 di-/trimethylation in the HFCD + P75 group. We, therefore, suggest that supplementation with PEITC may be a potential candidate for the treatment and prevention of atherosclerosis and obesity.     

Dimeric cinchona ammonium salts with benzophenone linkers: enantioselective phase transfer catalysts for the synthesis of α-amino acids

Chiral phase transfer catalysts of dimeric cinchona ammonium salts linked with a benzophenone bridge showed high enantioselectivity in the α-alkylation of a glycinate ester under mild industry-applicable conditions: 0.5 mol% PTC and near equivalents of alkyl halide. A dual function of the dimeric quinuclidiniums was proposed for the high efficiency.

Novel cinchona-alkaloid derived dimeric phase transfer catalysts (PTC) with benzophenone linkers and their α-alkylation of glycinate esters has been presented.

Since cinchona alkaloids were transformed to asymmetric quaternary quinuclidinium salts with benzyl halides and were used as a phase-transfer catalyst (PTC) (1) by Dolling¹ and O''Donnell,² cinchona alkaloids have been widely utilized as chiral templates for phase-transfer catalysis.³ (Scheme 1) These organic PTCs can be easily prepared from natural and low cost chiral cinchona alkaloids in a few synthetic steps and they are stable and facile under normal reaction conditions in water. Later N-9-anthracenylmethyl quinuclidinium salt PTC (2) was introduced and showed high enantioselectivity for the alkylation of the protected glycine tert-butyl ester.⁴ Quinuclidinium PTCs with each pseudo-enantiomeric cinchona alkaloids, such as (−)-cinchonidine and (+)-cinchonine, show enantiomeric selectivity each other, and have been successfully applied in various asymmetric organic synthesis including α-alkyl glycine derivatives synthesis.³Open in a separate windowScheme 1Representative cinchona-derived PTCs.Enantioselectivity in the alkylation of glycine esters has been probed by several experimental trials. Crystallographic study of the p-nitrophenoxide salt of PTC 2 showed that N-anthracenylmethy moiety of 2 is located in staggered position between the C^c and the C^d,^4a which provides more hindered spaces around the C^b–C^c–C^d face (F4) around the ammonium.⁵ The C^a–C^b–C^d face (F2) is blocked by O-allyl group and the C^a–C^c–C^d face (F3) are covered by bicyclic ring, but the C^a–C^b–C^c face (F1) is less hindered. Therefore, anionic glycinate derivatives could approach toward the F1. Enolates of glycine esters would form tight ionic complexes with the ammonium nitrogen on the F1 face of PTC 2, and the alkylation with alkyl halides could follow along the direction of less hindered side of the si/re-face of the enolates.^4aNOE correlations study of PTC 2 with borohydride ion⁶ indicated the borohydride occupies the F1 face of PTC 2. Computational simulation⁷ also described the stable transition states where an enolate locates on the F1 face.Dimeric cinchona-derived PTCs linked by either benzene or naphthalene ligand have been introduced by Park et al.^8a–c Among ortho, meta and para-connected PTCs, the meta-disubstituted phenyl PTC 3a or 2,7-disubstituted naphthyl PTC 3b showed highly improved catalytic effects compared to monomeric PTC 2, such as lower dosage of catalyst (1–5 mol%) and high enantioselectivity. Role of additional quinuclidinium was thought to be a steric blocker which could increase the stereoselectivity of the enolate complex on the F1 face.Other dimeric cinchona alkaloid PTCs were also developed with various linkers, such as 9,10-dimethylanthracenyl,⁹ biphenyl, alkenyl,¹⁰ macrocyclic amine and calixarene,¹¹ and their enantioselectivities were equal or lower than those of monomeric PTCs. Some dimeric PTCs were converted to ionic polymers by replacing bromides to a disufonate anion without loss of reactivity and enantioselectivity.¹²Alkylation of tert-butyl glycinate ester was performed with 1–10 mol% of PTC 1–3 and excess 5 equivalents of alkyl halide at 0 to −78 °C. These catalytic conditions are still to be improved for practical application; low mol% of PTC, near equimolar amount of alkyl halides and ambient temperature. Hence we investigated dimeric PTCs with various linkers for facile catalytic condition. Here we introduce new dimeric cinchona PTCs with a benzophenone linker and their application in asymmetric alkylation of glycine derivatives.Monomeric PTC 4p, N-(4-benzoylbenzyl)-O(9)-allylcinchonidium bromide, which has a benzoyl benzyl at N(1), was synthesized from 4-bromomethyl-benzophenone and (−)-cinchonidine. (Scheme 2) Dimeric cinchona-based quarternay ammonium salts (PTC 5–6) were synthesized from meta/para-di(bromomethyl) benzophenone¹³ and two equivalent cinchona alkaloids. Coupling reaction of the di(bromomethyl)benzophenone and (−)-cinchonidine or (+)-cinchonine in EtOH/DMF/CHCl₃ (5 : 6 : 2)⁸ for 5 h at 100 °C and the O(9)-allylation with allyl bromide gave the dimeric quarternary salts, bis(4-(O(9)-allyl-cinchonidium-N-methyl)phenyl) methanone dibromide (5) and bis(4-(O(9)-allyl-cinchonium-N-methyl)phenyl) methanone dibromide (6), respectively, in good yields.^‡Open in a separate windowScheme 2Monomeric and dimeric cinchona-PTC with a benzophenone bridge.Enantioselective PTC 4–6 system was applied in the alkylation of N-(diphenylmethylene)glycine tert-butyl ester (7) to the α-alkylated glycinate (8) under the condition of 0.5–1.0 mol% catalysts and 1.2 equivalent alkyl halides. We also explored the variation of enantioselectivity depending on the various positions of dimeric cinchonidium at benzophenone; 5pp, 5mp and 5mm.Monomeric PTC 4p showed enantioselectivity of 87% ee (S) at 25 °C (2 Geometric difference between PTC 1 and 4p is the extra p-benzoyl substituent on N-benzyl. Apparently the p-benzoyl moiety gives no big enhancement in enantioselectivity of 4p.Catalytic phase-transfer benzylation of 7 with monomeric and dimeric cinchona-based catalysts (4–6)^a

The power prior: theory and applications

The power prior has been widely used in many applications covering a large number of disciplines. The power prior is intended to be an informative prior constructed from historical data. It has been used in clinical trials, genetics, health care, psychology, environmental health, engineering, economics, and business. It has also been applied for a wide variety of models and settings, both in the experimental design and analysis contexts. In this review article, we give an A‐to‐Z exposition of the power prior and its applications to date. We review its theoretical properties, variations in its formulation, statistical contexts for which it has been used, applications, and its advantages over other informative priors. We review models for which it has been used, including generalized linear models, survival models, and random effects models. Statistical areas where the power prior has been used include model selection, experimental design, hierarchical modeling, and conjugate priors. Frequentist properties of power priors in posterior inference are established, and a simulation study is conducted to further examine the empirical performance of the posterior estimates with power priors. Real data analyses are given illustrating the power prior as well as the use of the power prior in the Bayesian design of clinical trials. Copyright © 2015 John Wiley & Sons, Ltd.     

Adjunctive Cilostazol versus High Maintenance Dose of Clopidogrel in Patients with Hyporesponsiveness to Chronic Clopidogrel Therapy

Purpose

Whether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown.

Materials and Methods

We studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35).

Results

Baseline percent inhibition of PRU and PRU was similar between 2 groups (13.0±10.2% versus 11.8±9.7%, p=0.61, and 286.3±54.7 versus 295.7±53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5±17.9% versus 28.3±16.6%, p=0.02, and 207.3±68.2 versus 241.3±76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7±8.7% to 15.8±18.4%, p=0.08, and from -18.6±58.0 to -61.9±84.3, p=0.08).

Conclusion

Adjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.     

Torsional Resistance of WaveOne Gold and Reciproc Blue according to the Loading Methods

IntroductionThis study aimed to compare the torsional resistances and fracture modes of WaveOne Gold (Dentsply Sirona, Ballaigues, Switzerland) and Reciproc Blue (VDW, Munich, Germany) using the repetitive torsional loading (RTL) method and the conventional single-rotation (STL) method.MethodsA 3-mm file tip was fixed with a brass plate, and a torsional load was applied using a custom device. In the RTL method, the file was driven counterclockwise at 50 rpm until it achieved the preset torque of 0.5 Ncm; thereafter, it was returned to its original position. This recovery of the file to its original position was defined as 1 torsional loading cycle; the number of repetitive load cycles until fracture was counted. In the STL method, the files were rotated at a constant rate of 2 rpm in a counterclockwise direction until file fracture. The fragments fractured by the 2 methods were compared under a scanning electron microscope to examine the topographic features of the fractured surfaces and longitudinal aspects.ResultsWith the RTL method, Reciproc Blue showed a higher number of repetitive load cycles until fracture than WaveOne Gold (P < .05). With the STL method, Reciproc Blue also had a higher ultimate strength than WaveOne Gold (P < .05). Scanning electron microscopic findings of the fractured specimens from the 2 test methods showed different features of torsional failure.ConclusionsWithin the study limitations, both the RTL and STL methods conferred similar torsional resistance. Therefore, the clinically relevant RTL method with repetitive and reciprocation motion can be used for testing torsional resistance.     

Health-Related Quality-of-Life after Percutaneous Coronary Intervention in Patients with UA/NSTEMI and STEMI: the Korean Multicenter Registry

Compared with ST elevation myocardial infarction (STEMI), long-term outcomes are known to be worse in patients with unstable angina/non-STEMI (UA/NSTEMI), which might be related to the worse health status of patients with UA/STEMI. In patients with UA/NSTEMI and STEMI underwent percutaneous coronary intervention (PCI), angina-specific and general health-related quality-of-life (HRQOL) was investigated at baseline and at 30 days after PCI. Patients with UA/NSTEMI were older and had higher frequencies in female, diabetes and hypertension. After PCI, both angina-specific and general HRQOL scores were improved, but improvement was much more frequent in angina-related HRQOL of patients with UA/NSTEMI than those with STEMI (44.2% vs 36.8%, P < 0.001). Improvement was less common in general HRQOL. At 30-days after PCI, angina-specific HRQOL of the patients with UA/NSTEMI was comparable to those with STEMI (56.1 ± 18.6 vs 56.6 ± 18.7, P = 0.521), but general HRQOL was significantly lower (0.86 ± 0.21 vs 0.89 ± 0.17, P = 0.001) after adjusting baseline characteristics (P < 0.001). In conclusion, the general health status of those with UA/NSTEMI was not good even after optimal PCI. In addition to angina-specific therapy, comprehensive supportive care would be needed to improve the general health status of acute coronary syndrome survivors.     

Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5′ flap DNA: basis of interstrand cross-link repair by FAN1

Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of Pseudomonas aeruginosa FAN1 (PaFAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5′ flap DNA. All four domains of the right-hand-shaped PaFAN1 are involved in DNA recognition, with each domain playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. PaFAN1 shares several conserved features with other flap structure-selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The PaFAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5′ flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair.     

Surgical suture assembled with polymeric drug-delivery sheet for sustained,local pain relief

Surgical suture is a strand of biocompatible material designed for wound closure, and therefore can be a medical device potentially suitable for local drug delivery to treat pain at the surgical site. However, the preparation methods previously introduced for drug-delivery sutures adversely influenced the mechanical strength of the suture itself – strength that is essential for successful wound closure. Thus, it is not easy to control drug delivery with sutures, and the drug-delivery surgical sutures available for clinical use are now limited to anti-infection roles. Here, we demonstrate a surgical suture enabled to provide controlled delivery of a pain-relief drug and, more importantly, we demonstrate how it can be fabricated to maintain the mechanical strength of the suture itself. For this purpose, we separately prepare a drug-delivery sheet composed of a biocompatible polymer and a pain-relief drug, which is then physically assembled with a type of surgical suture that is already in clinical use. In this way, the drug release profiles can be tailored for the period of therapeutic need by modifying only the drug-loaded polymer sheet without adversely influencing the mechanical strength of the suture. The drug-delivery sutures in this work can effectively relieve the pain at the surgical site in a sustained manner during the period of wound healing, while showing biocompatibility and mechanical properties comparable to those of the original surgical suture in clinical use.     

The Influence of Bone Tissue Deficiency on the Outcome of Endodontic Microsurgery: A Prospective Study

IntroductionThis study assessed the influence of deficiencies of the periapical and marginal bone tissue on clinical outcomes after endodontic microsurgery.MethodsData were collected from the Microscope Center of the Department of Conservative Dentistry at the Dental College of Yonsei University, Seoul, South Korea, between August 2004 and March 2011. In total, 199 teeth that required endodontic surgery were included in the study. During the surgical procedure, deficiencies of the periapical and marginal bone tissue were measured immediately before the flap was repositioned. The patients were recalled 6 months and 1 year after the surgical procedure to assess the clinical and radiographic signs of healing. The Student's t test or the Mann-Whitney U test and logistic regression were performed to evaluate the parameters. Significant associations between the outcome and all the evaluation parameters were analyzed using the Pearson chi-square test or the Fisher's exact test with a significance level of 0.05.ResultsA recall rate of 67.8% (135/199 teeth) was obtained. The height of the buccal bone plate was the only significant predictor (P = .040) of the healing outcome, suggesting that teeth with a buccal bone plate >3 mm presented a higher success rate than teeth with a buccal bone plate that was ≤3 mm high (94.3% vs 68.8%, P < .001).ConclusionsThese data suggest that a favorable prognosis can be expected when teeth are covered with a buccal bone plate that is >3 mm in height regardless of the amount of marginal bone loss.