bluuebunny/crossref_metadata_2025 huggingface dataset:
A Stereoselective Total Synthesis of Xyolide, a Natural Bioactive Nonenolide
Authors: Maram Lingaiah , Das Biswanath
Published: May 2015

A stereoselective total synthesis of xyolide, a naturally occurring bioactive nonenolide, has been accomplished. The acid fragment of the molecule has been prepared from D‐mannitol and the alcohol fragment from (2Z)‐but‐2‐ene‐1,4‐diol. The synthesis involves the coupling of these two fragments using the Yamaguchi esterification protocol, followed by intramolecular ring‐closing methathesis. The diastereoisomeric alcohol fragment has also been utilized in this synthesis by employing the Mitsunobu esterification.
Biflavonoids, Lignans, and Related Compounds from the Roots of Diplomorpha canescens
Authors: Prasad Devkota Hari , Raj Joshi Khem , Watanabe Takashi , Yahara Shoji
Published: May 2015

Two new biflavonoids, 14″‐O‐methyldihydrodaphnodorin B (1) and 14″‐O‐methyldaphnodorin J (2), along with 16 known compounds, i.e., dihydrodaphnodorin B (3), daphnodorin J (4), 3″‐epidihydrodaphnodorin B (5), daphnodorin B (6), neochamaejasmin B (7), sikokianin B (8), (−)‐syringaresinol (9), (−)‐syringaresinol 4‐O‐β‐D‐glucopyranoside (10), (+)‐nortrachelogenin (11), (−)‐lariciresinol (12), (−)‐pinoresinol (13), syringin (14), syringinoside (15), daphnoretin (16), phorbol 13‐acetate (17), and methyl paraben (18) were isolated from the roots of Diplomorpha canescens (Meisn.) C.A. Meyer. The structures were determined on the basis of spectroscopic data.
Menverins H–L, New Highly Oxygenated Guaiane Lactones from the Gorgonian Coral Menella kanisa
Authors: Yu Lian , Lin Lin , Long Bin , Chen Yinning , Lei Fu , Wen Liangjuan , Sun Haiyan , Gao Chenghai , Huang Riming
Published: May 2015

By further chemical investigation of South China Sea gorgonian Menella kanisa, five new highly oxygenated guaiane lactones, menverins H–L (1–5, resp.), were obtained. Their structures were established by employing spectroscopic methods, computer modeling, and comparison of their data with those of related metabolites.
Terpenoids from the Stems of Drypetes congestiflora
Authors: Chen Wen‐Hao , Han Chang‐Ri , Hui Yang , Zhang Da‐Shuai , Song Xin‐Ming , Chen Guang‐Ying , Song Xiao‐Ping
Published: May 2015

Two new eremophilane‐type sesquiterpenoids, 1α‐hydroxyeremophila‐6,9,11‐trien‐8‐one (1), 4α‐hydroxyeremophila‐1,9‐diene‐3,8‐dione (2), and a new friedelane‐type triterpenoid, friedelane‐3α,16β‐diol (4), along with six known terpenoids, 3 and 5–9, have been isolated from the stems of Drypetes congestiflora. Their structures and relative configurations were elucidated on the basis of detailed spectroscopic analyses and by comparison of their NMR data with those reported in the literature. All of the compounds, 1–9, were isolated for the first time from this species. Compound 3 exhibited moderate cytotoxic activities against the A549 and B16F10 cell lines.
Urine testing for antipsychotics: a pilot trial for a method to determine detection levels
Authors: Miller Jennifer , Wehring Heidi , McMahon Robert P. , DiPaula Bethany A. , Love Raymond C. , Morris Ayodele Antoinette , Raley Heather , Feldman Stephanie , Kelly Deanna L.
Published: May 2015

Objective

The goal of the present study was to demonstrate that the analytical assay of interest can detect antipsychotics in human urine specimens.

Method

Forty inpatients treated with haloperidol, quetiapine, risperidone, or olanzapine were recruited to participate in a one visit study. During the study visit, demographic and clinical information was collected as well as one urine sample that was forwarded to the Ameritox Laboratory and assayed for the presence of antipsychotic medications and/or metabolites. Urine samples were analyzed to determine detection sensitivity for four antipsychotic medications and their metabolites (risperidone, quetiapine, olanzapine, and/or haloperidol) using Ultra Performance Liquid Chromatography–Tandem Mass Spectrometry.

Results

All urine samples produced positive results for the antipsychotic(s) the participants were known to be taking. Urine concentrations (level of quantification) for parent drugs ranged from <25–417 ng/mL for haloperidol, <25–4017 ng/mL for quetiapine, 0–997 ng/mL for risperidone, and 57–700 ng/mL for olanzapine.

Conclusion

The analytical assay produced by Ameritox, Ltd using Ultra Performance Liquid Chromatography–Tandem Mass Spectrometry can qualitatively detect antipsychotics in human urine specimens. The present study highlights the potential utility of the urine assay to help monitor adherence to antipsychotic medications. Copyright © 2015 John Wiley & Sons, Ltd.
Short‐term, low‐dose cadmium exposure induces hyperpermeability in human renal glomerular endothelial cells
Authors: Li Liqun , Dong Fengyun , Xu Dongmei , Du Linna , Yan Suhua , Hu Hesheng , Lobe Corrinne G. , Yi Fan , Kapron Carolyn M. , Liu Ju
Published: May 2015

The kidney is the principal organ targeted by exposure to cadmium (Cd), a well‐known toxic metal. Even at a low level, Cd damages glomerular filtration. However, little is known about the effects of Cd on the glomerular endothelium, which performs the filtration function and directly interacts with Cd in blood plasma. In this study, we cultured human renal glomerular endothelial cells (HRGECs) in the presence of serum with treatment of a short term (1 h) and low concentration (1 μm) of Cd, which mimics the pattern of glomerular endothelium exposure to Cd in vivo. We found that this short‐term, low‐dose Cd exposure does not induce cytotoxicity, but increases permeability in HRGECs monolayers and redistributes adherens junction proteins vascular endothelial‐cadherin and β‐catenin. Though short‐term, low‐dose Cd exposure activates all three major mitogen activated protein kinases, only the inhibitor of p38 mitogen activated protein kinase partially prevents Cd‐induced hyperpermeability in HRGECs. Our data indicate that the presence of Cd in blood circulation might directly disrupt the glomerular endothelial cell barrier and contribute to the development of clinical symptoms of glomerular diseases. Copyright © 2015 John Wiley & Sons, Ltd.
Toxicogenomic responses of human liver HepG2 cells to silver nanoparticles
Authors: Sahu Saura C. , Zheng Jiwen , Yourick Jeffrey J. , Sprando Robert L. , Gao Xiugong
Published: May 2015

The increased use of silver nanoparticles (AgNPs) in foods and cosmetics has raised public safety concerns. However, only limited knowledge exists on the effect of AgNPs on the cellular transcriptome. This study evaluated global gene expression profiles of human liver HepG2 cells exposed to 20 and 50 nm AgNPs for 4 and 24 h at 2.5 µg ml–1. Exposure to 20 nm AgNPs resulted in 811 altered genes after 4 h, but much less after 24 h. Exposure to 50 nm AgNPs showed minimal altered genes at both exposure times. The HepG2 cells responded to the toxic insult of AgNPs by transiently upregulating stress response genes such as metallothioneins and heat shock proteins. Functional analysis of the altered genes showed more than 20 major biological processes were affected, of which metabolism, development, cell differentiation and cell death were the most dominant categories. Several cellular pathways were also impacted by AgNP exposure, including the p53 signaling pathway and the NRF2‐mediated oxidative stress response pathway, which may lead to increased oxidative stress and DNA damage in the cell and potentially result in genotoxicity and carcinogenicity. Together, these results indicate that HepG2 cells underwent a multitude of cellular processes in response to the toxic insult of AgNP exposure, and suggest that toxicogenomic characterization of human HepG2 cells could serve as an alternative model for assessing toxicities of NPs. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
EGF Inhibits Wnt/β‐Catenin‐Induced Osteoblast Differentiation by Promoting β‐Catenin Degradation
Authors: Boonanantanasarn Kanitsak , Lee Hye‐Lim , Baek Kyunghwa , Woo Kyung Mi , Ryoo Hyun‐Mo , Baek Jeong‐Hwa , Kim Gwan‐Shik
Published: May 2015

Bone morphogenetic protein (BMP) and canonical Wnts are representative developmental signals that enhance osteoblast differentiation and bone formation. Previously, we demonstrated that epidermal growth factor (EGF) inhibits BMP2‐induced osteoblast differentiation by inducing Smurf1 expression. However, the regulatory role of EGF in Wnt/β‐catenin‐induced osteoblast differentiation has not been elucidated. In this study, we investigated the effect of EGF on Wnt/β‐catenin signaling‐induced osteoblast differentiation using the C2C12 cell line. EGF significantly suppressed the expression of osteoblast marker genes, which were induced by Wnt3a and a GSK‐3β inhibitor. EGF increased the expression levels of Smurf1 mRNA and protein. Smurf1 knockdown rescued Wnt/β‐catenin‐induced osteogenic marker gene expression in the presence of EGF. EGF treatment or Smurf1 overexpression did not affect β‐catenin mRNA expression levels, but reduced β‐catenin protein levels and TOP‐Flash activity. EGF and Smurf1 promoted β‐catenin ubiquitination. Co‐immunoprecipitation and GST pull‐down assays showed that Smurf1 associates with β‐catenin. These results suggest that EGF/Smurf1 inhibits Wnt/β‐catenin‐induced osteogenic differentiation and that Smurf1 downregulates Wnt/β‐catenin signaling by enhancing proteasomal degradation of β‐catenin. J. Cell. Biochem. 116: 2849–2857, 2015. © 2015 Wiley Periodicals, Inc.
Platelet‐Rich Plasma Increases Growth and Motility of Adipose Tissue‐Derived Mesenchymal Stem Cells and Controls Adipocyte Secretory Function
Authors: D'Esposito Vittoria , Passaretti Federica , Perruolo Giuseppe , Ambrosio Maria Rosaria , Valentino Rossella , Oriente Francesco , Raciti Gregory A. , Nigro Cecilia , Miele Claudia , Sammartino Gilberto , Beguinot Francesco , Formisano Pietro
Published: May 2015

Adipose tissue‐derived mesenchymal stem cells (Ad‐MSC) and platelet derivatives have been used alone or in combination to achieve regeneration of injured tissues. We have tested the effect of platelet‐rich plasma (PRP) on Ad‐MSC and adipocyte function. PRP increased Ad‐MSC viability, proliferation rate and G1‐S cell cycle progression, by at least 7‐, 2‐, and 2.2‐fold, respectively, and reduced caspase 3 cleavage. Higher PRP concentrations or PRPs derived from individuals with higher platelet counts were more effective in increasing Ad‐MSC growth. PRP also accelerated cell migration by at least 1.5‐fold. However, PRP did not significantly affect mature adipocyte viability, differentiation and expression levels of PPAR‐γ and AP‐2 mRNAs, while it increased leptin production by 3.5‐fold. Interestingly, PRP treatment of mature adipocytes also enhanced the release of Interleukin (IL)‐6, IL‐8, IL‐10, Interferon‐γ, and Vascular Endothelial Growth Factor. Thus, data are consistent with a stimulatory effect of platelet derivatives on Ad‐MSC growth and motility. Moreover, PRP did not reduce mature adipocyte survival and increased the release of pro‐angiogenic factors, which may facilitate tissue regeneration processes. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc. J. Cell. Biochem. 116: 2408–2418, 2015. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.
The Effects of miR‐20a on p21: Two Mechanisms Blocking Growth Arrest in TGF‐β‐Responsive Colon Carcinoma
Authors: Sokolova Viktorija , Fiorino Antonio , Zoni Eugenio , Crippa Elisabetta , Reid James F. , Gariboldi Manuela , Pierotti Marco A.
Published: May 2015

Loss of response to TGF‐β is a central event in the genesis of colorectal cancer (CRC), a disease that, in the majority cases, is refractory to growth inhibition induced by this cytokine. However, inactivating mutations at receptors and transducers from the TGF‐β cascade occur only in approximately half of CRCs, suggesting the involvement of additional mechanisms altering the response to the cytokine. We have recently described the amplification of the 13q31 locus, where the miR‐17–92 cluster maps, associated with overexpression of its members. In this study, we address the potential role of miR‐20a, from the miR‐17–92 cluster, in the suppression of TGF‐β cytostatic response in CRC. Using the poorly tumorigenic and TGF‐β‐sensitive FET cell line that expresses low miR‐20a levels, we first confirmed that miR‐20a downmodulated CDKN1A expression, both at mRNA and protein level, through direct binding to its 3′‐UTR. We demonstrated that miR‐20a significantly diminished cell response to TGF‐β by preventing its delay of G1/S transition and promoting progression into cell cycle. Moreover, besides modulating CDKN1A, miR‐20a blocked TGF‐β‐induced transactivation of its promoter without affecting the post‐receptor activation of Smad3/4 effectors directly. Finally, miR‐20a abrogated the TGF‐β‐mediated c‐Myc repression, a direct inhibitor of the CDKN1A promoter activation, most likely by reducing the expression of specific MYC‐regulating genes from the Smad/E2F‐based core repressor complex. Our experiments indicate that miR‐20a interferes with the colonic epithelium homeostasis by disrupting the regulation of Myc/p21 by TGF‐β, which is essential for its malignant transformation. J. Cell. Physiol. 230: 3105–3114, 2015. © 2015 Wiley Periodicals, Inc.
The characteristics of patients frequently admitted to academic medical centers in the United States
Authors: Szekendi Marilyn K. , Williams Mark V. , Carrier Danielle , Hensley Laurie , Thomas Stephen , Cerese Julie
Published: May 2015

BACKGROUND

The recent intense attention to hospital readmissions and their implications for quality, safety, and reimbursement necessitates understanding specific subsets of readmitted patients. Frequently admitted patients, defined as patients who are admitted 5 or more times within 1 year, may have some distinguishing characteristics that require novel solutions.

METHODS

A comprehensive administrative database (University HealthSystem Consortium's Clinical Data Base/Resource Manager™) was analyzed to identify demographic, social, and clinical characteristics of frequently admitted patients in 101 US academic medical centers.

RESULTS

We studied 28,291 frequently admitted patients with 180,185 admissions over a 1‐year period (2011–2012). These patients comprise 1.6% of all patients, but account for 8% of all admissions and 7% of direct costs. Their admissions are driven by multiple chronic conditions; compared to other hospitalized patients, they have significantly more comorbidities (an average of 7.1 vs 2.5), and 84% of their admissions are to medical services. A minority, but significantly more than other patients, have comorbidities of psychosis or substance abuse. Moreover, although they are slightly more likely than other patients to be on Medicaid or to be uninsured (27.6% vs 21.6%), nearly three‐quarters have private or Medicare coverage.

CONCLUSIONS

Patients who are frequently admitted to US academic medical centers are likely to have multiple complex chronic conditions and may have behavioral comorbidities that mediate their health behaviors, resulting in acute episodes requiring hospitalization. This information can be used to identify solutions for preventing repeat hospitalization for this small group of patients who consume a highly disproportionate share of healthcare resources. Journal of Hospital Medicine 2015;10:563–568. © 2015 The Authors Journal of Hospital Medicine published by Wiley Periodicals, Inc. on behalf of Society of Hospital Medicine
Variation in printed handoff documents: Results and recommendations from a multicenter needs assessment
Authors: Rosenbluth Glenn , Bale James F. , Starmer Amy J. , Spector Nancy D. , Srivastava Rajendu , West Daniel C. , Sectish Theodore C. , Landrigan Christopher P. ,   I‐PASS Study Education Executive Committee
Published: May 2015

BACKGROUND

Handoffs of patient care are a leading root cause of medical errors. Standardized techniques exist to minimize miscommunications during verbal handoffs, but studies to guide standardization of printed handoff documents are lacking.

OBJECTIVE

To determine whether variability exists in the content of printed handoff documents and to identify key data elements that should be uniformly included in these documents.

SETTING

Pediatric hospitalist services at 9 institutions in the United States and Canada.

METHODS

Sample handoff documents from each institution were reviewed, and structured group interviews were conducted to understand each institution's priorities for written handoffs. An expert panel reviewed all handoff documents and structured group‐interview findings, and subsequently made consensus‐based recommendations for data elements that were either essential or recommended, including best overall printed handoff practices.

RESULTS

Nine sites completed structured group interviews and submitted data. We identified substantial variation in both the structure and content of printed handoff documents. Only 4 of 23 possible data elements (17%) were uniformly present in all sites' handoff documents. The expert panel recommended the following as essential for all printed handoffs: assessment of illness severity, patient summary, action items, situation awareness and contingency plans, allergies, medications, age, weight, date of admission, and patient and hospital service identifiers. Code status and several other elements were also recommended.

CONCLUSIONS

Wide variation exists in the content of printed handoff documents. Standardizing printed handoff documents has the potential to decrease omissions of key data during patient care transitions, which may decrease the risk of downstream medical errors. Journal of Hospital Medicine 2015;10:517–524. © 2015 Society of Hospital Medicine
Associations between teaching effectiveness scores and characteristics of presentations in hospital medicine continuing education
Authors: Ratelle John T. , Wittich Christopher M. , Yu Roger C. , Newman James S. , Jenkins Sarah M. , Beckman Thomas J.
Published: May 2015

BACKGROUND

There is little research regarding characteristics of effective continuing medical education (CME) presentations in hospital medicine (HM). Therefore, we sought to identify associations between validated CME teaching effectiveness scores and characteristics of CME presentations in the field of HM.

DESIGN/SETTING

This was a cross‐sectional study of participants and didactic presentations from a national HM CME course in 2014.

MEASUREMENTS

Participants provided CME teaching effectiveness (CMETE) ratings using an instrument with known validity evidence. Overall CMETE scores (5‐point scale: 1 = strongly disagree; 5 = strongly agree) were averaged for each presentation, and associations between scores and presentation characteristics were determined using the Kruskal‐Wallis test. The threshold for statistical significance was set at P < 0.05.

RESULTS

A total of 277 out of 368 participants (75.3%) completed evaluations for the 32 presentations. CMETE scores (mean [standard deviation]) were significantly associated with the use of audience response (4.64 [0.16]) versus no audience response (4.49 [0.16]; P = 0.01), longer presentations (≥30 minutes: 4.67 [0.13] vs <30 minutes: 4.51 [0.18]; P = 0.02), and larger number of slides (≥50: 4.66 [0.17] vs <50: 4.55 [0.17]; P = 0.04). There were no significant associations between CMETE scores and use of clinical cases, defined goals, or summary slides.

CONCLUSIONS

To our knowledge, this is the first study regarding associations between validated teaching effectiveness scores and characteristics of effective CME presentations in HM. Our findings, which support previous research in other fields, indicate that CME presentations may be improved by increasing interactivity through the use of audience response systems and allowing longer presentations. Journal of Hospital Medicine 2015;10:569–573. © 2015 Society of Hospital Medicine
Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties
Authors: Xu Ruixue , Zhan Miao , Peng Lingling , Pang Xuehai , Yang Jun , Zhang Tao , Jiang Hongxia , Zhao Lifeng , Chen Yuanwei
Published: May 2015

Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB‐C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB‐C2202.
Regional anisotropy of airspace orientation in the lung as assessed with hyperpolarized helium‐3 diffusion MRI
Authors: Komlosi Peter , Altes Talissa A. , Qing Kun , Mooney Karen E. , Miller G. Wilson , Mata Jaime F. , de Lange Eduard E. , Tobias William A. , Cates Gordon D. , Brookeman James R. , Mugler John P.
Published: May 2015

Purpose

To evaluate regional anisotropy of lung‐airspace orientation by assessing the dependence of helium‐3 (3He) apparent diffusion coefficient (ADC) values on the direction of diffusion sensitization at two field strengths.

Materials and Methods

Hyperpolarized 3He diffusion‐weighted magnetic resonance imaging (MRI) of the lung was performed at 0.43T and 1.5T in 12 healthy volunteers. A gradient‐echo pulse sequence was used with a bipolar diffusion‐sensitization gradient applied separately along three orthogonal directions. ADC maps, median ADC values, and signal‐to‐noise ratios were calculated from the diffusion‐weighted images. Two readers scored the ADC maps for increased values at lung margins, major fissures, or within focal central regions.

Results

ADC values were found to depend on the direction of diffusion sensitization (P < 0.01, except for craniocaudal vs. anteroposterior directions at 1.5T) and were increased at the lateral and medial surfaces for left‐right diffusion sensitization (12 of 12 subjects); at the apex and base (9 of 12), and along the major fissure (8 of 12), for craniocaudal diffusion sensitization; and at the most anterior and posterior lung (10 of 12) for anteroposterior diffusion sensitization. Median ADC values at 0.43T (0.201 ± 0.017, left‐right; 0.193 ± 0.019, craniocaudal; and 0.187 ± 0.017 cm2/s, anteroposterior) were slightly lower than those at 1.5T (0.205 ± 0.017, 0.197 ± 0.017 and 0.194 ± 0.016 cm2/s, respectively; P < 0.05).

Conclusion

These findings indicate that diffusion‐weighted hyperpolarized 3He MRI can detect regional anisotropy of lung‐airspace orientation, including that associated with preferential orientation of terminal airways near pleural surfaces. J. MAGN. RESON. IMAGING 2015;42:1777–1782.
Structural elucidation and estimation of the acute toxicity of the major UV–visible photoproduct of fludioxonil – detection in both skin and flesh samples of grape
Authors: Lassalle Yannick , Nicol Édith , Genty Christophe , Bourcier Sophie , Bouchonnet Stéphane
Published: May 2015

Ultraviolet (UV)–visible irradiation of fludioxonil was investigated with two photoreactors using either a mercury or xenon vapor lamp. In both cases, it led to the formation of only one photoproduct in significant amount: 2‐(2,2‐difluorobenzo[d][1,3]dioxol‐4‐yl)‐2‐(nitrosomethylene)‐4‐oxobutanenitrile, which has been characterized using Liquid Chromatography ‐ High Resolution ‐ Tandem Mass Spectrometry (LC‐HR‐MS/MS) coupling. A photolysis pathway has been proposed to rationalize its formation in degassed water. In vitro bioassays on Vibrio fischeri bacteria showed that UV–vis irradiation of an aqueous solution of fludioxonil significantly increases its toxicity. Because no other by‐product was detected in significant amount, the photoproduct mentioned above may be considered mainly responsible for this increase in toxicity. Grape berries treated with a 50 ppm aqueous solution of fludioxonil were submitted to UV–visible irradiation under laboratory conditions. The fungicide and photoproduct were detected in both skin and flesh of berries, even after they have been rinsed with water. The ability of the photoproduct to pass through the fruit skin is comparable with that of fludioxonil. These results are of concern for consumers because they mean that water tap rinsing does not lead to efficient removing of both compounds. Copyright © 2015 John Wiley & Sons, Ltd.
Effect of zoledronic acid on spinal fusion outcomes in an ovariectomized rat model of osteoporosis
Authors: Yasen Miersalijiang , Li Xiangqian , Jiang Libo , Yuan Wei , Che Wu , Dong Jian
Published: May 2015

To evaluate the effect of zoledronic acid (ZA) on spinal fusion in ovariectomized (OVX) rats. Female SD rats (n = 50) were OVX or sham‐operated and randomized into five groups: Sham, OVX control, ZOL‐20 (20 µg/kg), ZOL‐100 (100 µg/kg), and ZOL‐500 (500 µg/kg). Eight weeks after OVX, bilateral lumbar spinal fusion was performed using autologous iliac bone with ZA or saline according to the grouping. The lumbar spines were harvested at 8 weeks and subjected to radiographic, manual palpation, micro‐computed tomographic (micro‐CT), and histological analysis. The manual palpation result differed significantly only between the ZOL‐500 (fused: partially fused: not fused, 9:0:0) and OVX control (4:2:3) (p < 0.05). The radiographic scales were also differed significantly only between these two groups. According to the micro‐CT results, the bone volume fraction (BV/TV) were significantly higher in all ZA‐treated groups (54.2%, 65.9%, and 73.6%) than OVX control (43.7%) (p < 0.01). At clinical dose or lower, ZA didn't alter the spinal fusion, but a higher dose increased the spinal fusion rate significantly. This study suggests ZA may have a positive effect on spinal fusion in the presence of osteoporosis, and spinal fusion surgery outcome is not likely to be altered by ZA at clinical dose. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1297–1304, 2015.
Surgical margins and primary site resection in achieving local control in oral cancer resections
Authors: Varvares Mark A. , Poti Shannon , Kenyon Bianca , Christopher Kara , Walker Ronald J.
Published: May 2015

Objectives/Hypothesis

Evaluate effectiveness of resection of oral cavity cancer with a standardized approach for margin evaluation. Primary end points were local control and survival.

Study Design

Retrospective, nonrandomized, single institution.

Methods

One hundred eight patients who underwent surgery for oral cancer were evaluated using specific anatomical pathology criteria. Frozen section was performed with the surgeon and pathologist agreeing where on the specimen the frozen sections should be taken in most cases.

Results

Ninety‐one patients (84.3%) had frozen sections taken from the specimen, eight from the tumor bed, and nine had none taken at the time of surgery. Overall local recurrence rate was 18.5%, 25% in patients who had margins taken from the tumor bed and 17.6% when taken from the specimen. Twenty‐nine patients had margins ≥5 mm, 53 <5 mm and clear, and 14 positive re‐resected to negative with local recurrence rates of 3.4%, 26.4%, and 28.6%, respectively. The radial distance of the resection margin was shown to have an impact on overall survival (hazard ratio [HR] = 3.59, 95% confidence interval [CI] = 1.12‐11.57), disease‐free survival (HR = 7.00, 95% CI = 1.89‐25.95), and local recurrence‐free survival (HR = 28.80, 95% CI = 3.00–276.82).

Conclusions

Assessing margins from the resection specimen rather than the tumor bed consistently predicts local control. There is a statistical improvement in local control, disease‐free, and overall survival with increasing radial margin distance from the tumor, and 5 mm should be agreed upon as the definition of a clear resection margin. Frozen sections can be used to revise positive or close resection margins intraoperatively with improved outcomes.

Level of Evidence

4. Laryngoscope, 125:2298–2307, 2015
Monomers for Adhesive Polymers, 16 Synthesis of Acidic Dimethacrylates Starting from Thioglycerol
Authors: Catel Yohann , Schörpf Sebastian , Moszner Norbert
Published: May 2015

Six novel acidic monomers were synthesized in three to six steps, starting from thioglycerol. Four phosphonic acids, a dihydrogen phosphate, and a bisphosphonic acid were prepared. They were characterized by 1H‐NMR, 13C‐NMR, 31P‐NMR spectroscopy, and by HRMS. Their free radical polymerization was carried out in a water/ethanol solution, using 2,2′‐azobis(2‐methylpropionamidine) dihydrochloride as an initiator. Photopolymerization of these acidic monomers as well as of their corresponding diethyl phosphonates and phosphates was investigated using photo‐DSC. Self‐etch adhesives were formulated and used to mediate a bond between the dental hard tissues and a composite. Dentin and enamel shear bond strength tests showed that each acidic monomer was able to provide a good adhesion. The adhesive based on the bisphosphonic acid monomer led to the best adherence.
Guidelines for the Synthesis of Block Copolymer Particles of Various Morphologies by RAFT Dispersion Polymerization
Authors: Rieger Jutta
Published: May 2015

This article presents the recent developments of radical dispersion polymerizaton controlled by reversible addition fragmentation chain transfer (RAFT) for the production of block copoly­mer particles of various morphologies, such as core‐shell spheres, worms, or vesicles. It is not meant to be an exhaustive review but it rather provides guidelines for non‐specialists. The article is subdivided into eight sections. After a general introduction, the mechanism of polymerization‐induced self‐assembly (PISA) through RAFT‐mediated dispersion polymerization is presented and the different parameters that control the morphology produced are discussed. The next two sections are devoted to the choice of the monomer/solvent pair and the macroRAFT agent. Afterwards, post‐polymerization morphological order‐to‐order transitions (i.e. morphological transitions triggered by extrinsic stimuli) or order‐to‐disorder transitions (i.e. disassembly of chains) are discussed. Assemblies based on more complex polymer architectures, such as triblock copolymers, are presented next, and finally the possibility to stabilize these structures by crosslinking is reported. The manuscript ends with a short conclusion and an outlook.

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Up to 100% Improvement in Dynamic Nuclear Polarization Solid‐State NMR Sensitivity Enhancement of Polymers by Removing Oxygen
Authors: Le Dao , Ziarelli Fabio , Phan Trang N. T. , Mollica Giulia , Thureau Pierre , Aussenac Fabien , Ouari Olivier , Gigmes Didier , Tordo Paul , Viel Stéphane
Published: May 2015

High‐field dynamic nuclear polarization (DNP) has emerged as a powerful technique for improving the sensitivity of solid‐state NMR (SSNMR), yielding significant sensitivity enhancements for a variety of samples, including polymers. Overall, depending upon the type of polymer, the molecular weight, and the DNP sample preparation method, sensitivity enhancements between 5 and 40 have been reported. These promising enhancements remain, however, far from the theoretical maximum (>1000). Crucial to the success of DNP SSNMR is the DNP signal enhancement (εDNP), which is the ratio of the NMR signal intensities with and without DNP. It is shown here that, for polymers exhibiting high affinity toward molecular oxygen (e.g., polystyrene), removing part of the absorbed (paramagnetic) oxygen from the solid‐state samples available as powders (instead of dissolved or dispersed in a solvent) increases proton nuclear relaxation times and εDNP, hereby providing up to a two‐fold sensitivity increase (i.e., a four‐fold reduction in experimental time).

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Theoretical Consideration of Phase Behavior of the Products of Free‐Radical Copolymerization Described by the Penultimate Model
Authors: Kuchanov Semion I. , Bogdanov Artem N. , Tarasevich Konstantin V.
Published: May 2015

The penultimate model of copolymerization taking into account the dependence of the reactivity of a macroradical on the type of the unit preceding the ultimate one is well‐known in polymer chemistry. All types of chemical structure of multiblock copolymers capable to form during copolymerization processes described by such a model are revealed in the present work. Phase diagrams of copolymers of all these types specifying the regions of thermodynamic stability of spatially periodic mesophases differing in morphology are constructed in the framework of the weak segregation theory. Besides, the periods and amplitudes of the variation of different type densities of units in mesophases as well as volume fractions of these latter within the regions of their coexistence are calculated.
Signature of protein unfolding in chemical exchange saturation transfer imaging
Authors: Goerke Steffen , Zaiss Moritz , Kunz Patrick , Klika Karel D. , Windschuh Johannes D. , Mogk Axel , Bukau Bernd , Ladd Mark E. , Bachert Peter
Published: May 2015

Chemical exchange saturation transfer (CEST) allows the detection of metabolites of low concentration in tissue with nearly the sensitivity of MRI with water protons. With this spectroscopic imaging approach, several tissue‐specific CEST effects have been observedin vivo. Some of these originate from exchanging sites of proteins, such as backbone amide protons, or from aliphatic protons within the hydrophobic protein core. In this work, we employed CEST experiments to detect global protein unfolding. Spectral evaluation revealed exchange‐ and NOE‐mediated CEST effects that varied in a highly characteristic manner with protein unfolding tracked by fluorescence spectroscopy. We suggest the use of this comprehensive spectral signature for the detection of protein unfolding by CEST, as it relies on several spectral hallmarks. As proof of principle, we demonstrate that the presented signature is readily detectable using a whole‐body MR tomograph (B0 = 7 T), not only in denatured aqueous protein solutions, but also in heat‐shocked yeast cells. A CEST imaging contrast with the potential to detect global protein unfolding would be of particular interest regarding protein unfolding as a marker for stress, ageing, and disease. Copyright © 2015 John Wiley & Sons, Ltd.
Cerebrovascular MRI: a review of state‐of‐the‐art approaches, methods and techniques
Authors: MacDonald Matthew Ethan , Frayne Richard
Published: May 2015

Cerebrovascular imaging is of great interest in the understanding of neurological disease. MRI is a non‐invasive technology that can visualize and provide information on: (i) the structure of major blood vessels; (ii) the blood flow velocity in these vessels; and (iii) the microcirculation, including the assessment of brain perfusion. Although other medical imaging modalities can also interrogate the cerebrovascular system, MR provides a comprehensive assessment, as it can acquire many different structural and functional image contrasts whilst maintaining a high level of patient comfort and acceptance. The extent of examination is limited only by the practicalities of patient tolerance or clinical scheduling limitations. Currently, MRI methods can provide a range of metrics related to the cerebral vasculature, including: (i) major vessel anatomy via time‐of‐flight and contrast‐enhanced imaging; (ii) blood flow velocity via phase contrast imaging; (iii) major vessel anatomy and tissue perfusion via arterial spin labeling and dynamic bolus passage approaches; and (iv) venography via susceptibility‐based imaging. When designing an MRI protocol for patients with suspected cerebral vascular abnormalities, it is appropriate to have a complete understanding of when to use each of the available techniques in the ‘MR angiography toolkit’. In this review article, we: (i) overview the relevant anatomy, common pathologies and alternative imaging modalities; (ii) describe the physical principles and implementations of the above listed methods; (iii) provide guidance on the selection of acquisition parameters; and (iv) describe the existing and potential applications of MRI to the cerebral vasculature and diseases. The focus of this review is on obtaining an understanding through the application of advanced MRI methodology of both normal and abnormal blood flow in the cerebrovascular arteries, capillaries and veins. Copyright © 2015 John Wiley & Sons, Ltd.
Generalized finite element approaches for analysis of localized thermo‐structural effects
Authors: Plews J.A. , Duarte C.A.
Published: May 2015

This work addresses computational modeling challenges associated with structures subjected to sharp, local heating, where complex temperature gradients in the materials cause three‐dimensional, localized, intense stress and strain variation. Because of the nature of the applied loadings, multiphysics analysis is necessary to accurately predict thermal and mechanical responses. Moreover, bridging spatial scales between localized heating and global responses of the structure is nontrivial. A large global structural model may be necessary to represent detailed geometry alone, and to capture local effects, the traditional approach of pre‐designing a mesh requires careful manual effort. These issues often lead to cumbersome and expensive global models for this class of problems. To address them, the authors introduce a generalized FEM (GFEM) approach for analyzing three‐dimensional solid, coupled physics problems exhibiting localized heating and corresponding thermomechanical effects. The capabilities of traditional hp‐adaptive FEM or GFEM as well as the GFEM with global–local enrichment functions are extended to one‐way coupled thermo‐structural problems, providing meshing flexibility at local and global scales while remaining competitive with traditional approaches. The methods are demonstrated on several example problems with localized thermal and mechanical solution features, and accuracy and (parallel) computational efficiency relative to traditional direct modeling approaches are discussed. Copyright © 2015 John Wiley & Sons, Ltd.
An efficient binning scheme with application to statistical crack mechanics
Authors: Huq F. , Brannon R. , Graham‐Brady L.
Published: May 2015

A computational scheme is developed for sampling‐based evaluation of a function whose inputs are statistically variable. After a general abstract framework is developed, it is applied to initialize and evolve the size and orientation of cracks within a finite domain, such as a finite element or similar subdomain. The finite element is presumed to be too large to explicitly track each of the potentially thousands (or even millions) of individual cracks in the domain. Accordingly, a novel binning scheme is developed that maps the crack data to nodes on a reference grid in probability space. The scheme, which is clearly generalizable to applications involving arbitrary numbers of random variables, is illustrated in the scope of planar deformations of a brittle material containing straight cracks. Assuming two random variables describe each crack, the cracks are assigned uniformly random orientations and non‐uniformly random sizes. Their data are mapped to a computationally tractable number of nodes on a grid laid out in the unit square of probability space so that Gauss points on the grid may be used to define an equivalent subpopulation of the cracks. This significantly reduces the computational cost of evaluating ensemble effects of large evolving populations of random variables. Copyright © 2015 John Wiley & Sons, Ltd.
Propensity score matching and persistence correction to reduce bias in comparative effectiveness: the effect of cinacalcet use on all‐cause mortality
Authors: Gillespie Iain A. , Floege Jürgen , Gioni Ioanna , Drüeke Tilman B. , de Francisco Angel L. , Anker Stefan D. , Kubo Yumi , Wheeler David C. , Froissart Marc ,   on behalf the ARO Steering Committee collaborators
Published: May 2015

Purpose

The generalisability of randomised controlled trials (RCTs) may be limited by restrictive entry criteria or by their experimental nature. Observational research can provide complementary findings but is prone to bias. Employing propensity score matching, to reduce such bias, we compared the real‐life effect of cinacalcet use on all‐cause mortality (ACM) with findings from the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) RCT in chronic haemodialysis patients.

Methods

Incident adult haemodialysis patients receiving cinacalcet, recruited in a prospective observational cohort from 2007–2009 (AROii; n = 10,488), were matched to non‐exposed patients regardless of future exposure status. The effect of treatment crossover was investigated with inverse probability of censoring weighted and lag‐censored analyses. EVOLVE ACM data were analysed largely as described for the primary composite endpoint.

Results

AROii patients receiving cinacalcet (n = 532) were matched to 1790 non‐exposed patients. The treatment effect of cinacalcet on ACM in the main AROii analysis (hazard ratio 1.03 [95% confidence interval (CI) 0.78–1.35]) was closer to the null than for the Intention to Treat (ITT) analysis of EVOLVE (0.94 [95%CI 0.85–1.04]). Adjusting for non‐persistence by 0‐ and 6‐month lag‐censoring and by inverse probability of censoring weight, the hazard ratios in AROii (0.76 [95%CI 0.51–1.15], 0.84 [95%CI 0.60–1.18] and 0.79 [95%CI 0.56–1.11], respectively) were comparable with those of EVOLVE (0.82 [95%CI 0.67–1.01], 0.83 [95%CI 0.73–0.96] and 0.87 [95%CI 0.71–1.06], respectively).

Conclusions

Correcting for treatment crossover, we observed results in the ‘real‐life’ setting of the AROii observational cohort that closely mirrored the results of the EVOLVE RCT. Persistence‐corrected analyses revealed a trend towards reduced ACM in haemodialysis patients receiving cinacalcet therapy. © 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.
An integrative approach combining ion mobility mass spectrometry, X‐ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1‐antitrypsin upon ligand binding
Authors: Nyon Mun Peak , Prentice Tanya , Day Jemma , Kirkpatrick John , Sivalingam Ganesh N. , Levy Geraldine , Haq Imran , Irving James A. , Lomas David A. , Christodoulou John , Gooptu Bibek , Thalassinos Konstantinos
Published: May 2015

Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)‐MS can report on conformational behavior of specific states. We used IM‐MS to study a conformationally labile protein (α1‐antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z‐variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild‐type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z α1‐antitrypsin polymerogenicity. We show the ability of IM‐MS to track such disease‐relevant conformational behavior in detail by studying the effects of peptide binding on α1‐antitrypsin conformation and dynamics. IM‐MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native α1‐antitrypsin. Our findings are confirmed with high‐resolution X‐ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue‐specific level. IM‐MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest.
Protonation states and catalysis: Molecular dynamics studies of intermediates in tryptophan synthase
Authors: Huang Yu‐ming M. , You Wanli , Caulkins Bethany G. , Dunn Michael F. , Mueller Leonard J. , Chang Chia‐en A.
Published: May 2015

The importance of protonation states and proton transfer in pyridoxal 5’‐phosphate (PLP)‐chemistry can hardly be overstated. Although experimental approaches to investigate pKa values can provide general guidance for assigning proton locations, only static pictures of the chemical species are available. To obtain the overall protein dynamics for the interpretation of detailed enzyme catalysis in this study, guided by information from solid‐state NMR, we performed molecular dynamics (MD) simulations for the PLP‐dependent enzyme tryptophan synthase (TRPS), whose catalytic mechanism features multiple quasi‐stable intermediates. The primary objective of this work is to elucidate how the position of a single proton on the reacting substrate affects local and global protein dynamics during the catalytic cycle. In general, proteins create a chemical environment and an ensemble of conformational motions to recognize different substrates with different protonations. The study of these interactions in TRPS shows that functional groups on the reacting substrate, such as the phosphoryl group, pyridine nitrogen, phenolic oxygen and carboxyl group, of each PLP‐bound intermediate play a crucial role in constructing an appropriate molecular interface with TRPS. In particular, the protonation states of the ionizable groups on the PLP cofactor may enhance or weaken the attractions between the enzyme and substrate. In addition, remodulation of the charge distribution for the intermediates may help generate a suitable environment for chemical reactions. The results of our study enhance knowledge of protonation states for several PLP intermediates and help to elucidate their effects on protein dynamics in the function of TRPS and other PLP‐dependent enzymes.
First‐principles study on alkali‐metal effect of Li, Na, and K in Cu2ZnSnS4 and Cu2ZnSnSe4
Authors: Maeda Tsuyoshi , Kawabata Atsuhito , Wada Takahiro
Published: May 2015

The substitution energies and migration energies of the alkali‐metals of Li, Na, and K atoms in Cu2ZnSnS4 (CZTS) and Cu2ZnSnSe4 (CZTSe) were investigated by first‐principles calculations. The migration energies of Li, Na, and K atoms in CZTS and CZTSe are obtained by a combination of linear and quadratic synchronous transit (LST/QST) methods and a nudged elastic band (NEB) method. For CZTS and CZTSe, the substitution energies of NaCu and NaZn are much smaller than that of NaSn. The substitution energy of NaZn is comparable to that of NaCu, indicating that NaCu and NaZn are easily formed in CZTS and CZTSe. The substitution energies of the LiCu and LiZn atoms are smaller than those of NaCu and NaZn, while substitution energies of KCu and KZn atoms are much larger than those of NaCu and NaZn. Therefore, it is difficult to form KCu and KZnin CZTS and CZTSe. The theoretical migration energies of Na atom at Cu site to the nearest Cu vacancy (NaCu→VCu) and Na atom at Zn site to the nearest Cu vacancy (NaZn→VCu) are much smaller than those of (NaSn→VCu). The migration energies of (NaCu→VCu) and (NaZn→VCu) in CZTS and CZTSe are comparable to that of Na atom at Cu site to Cu vacancy (NaCu→VCu) in CIS. The mechanism for the alkali‐metal effect of Li, Na, and K in the Cu2ZnSn(S,Se)4 films during the post‐deposition treatment of LiF, NaF, and KF is discussed on the basis of the calculated substitution and migration energies. (© 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)