bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial variation in the quality of surgical care for bladder cancer
Authors: Barocas Daniel A. , Alvarez JoAnn , Koyama Tatsuki , Anderson Christopher B. , Gray Darryl T. , Fowke Jay H. , You Chaochen , Chang Sam S. , Cookson Michael S. , Smith Joseph A. , Penson David F.
Published: December 2013

BACKGROUND

Differences in quality of care may contribute to racial variation in outcomes of bladder cancer (BCa). Quality indicators in patients undergoing surgery for BCa include the use of high‐volume surgeons and high‐volume hospitals, and, when clinically indicated, receipt of pelvic lymphadenectomy, receipt of continent urinary diversion, and undergoing radical cystectomy instead of partial cystectomy. The authors compared these quality indicators as well as adverse perioperative outcomes in black patients and white patients with BCa.

METHODS

The Healthcare Cost and Utilization Project State Inpatient Databases for New York, Florida, and Maryland (1996‐2009) were used, because they consistently included race, surgeon, and hospital identifiers. Quality indicators were compared across racial groups using regression models adjusting for age, sex, Elixhauser comorbidity sum, insurance, state, and year of surgery, accounting for clustering within hospital.

RESULTS

Black patients were treated more often by lower volume surgeons and hospitals, they had significantly lower receipt of pelvic lymphadenectomy and continent diversion, and they experienced higher rates of adverse outcomes compared with white patients. These associations remained significant for black patients who received treatment from surgeons and at hospitals in the top volume decile.

CONCLUSIONS

Black patients with BCa had lower use of experienced providers and institutions for BCa surgery. In addition, the quality of care for black patients was lower than that for whites even if they received treatment in a high‐volume setting. This gap in quality of care requires further investigation. Cancer 2014;120:1018–1025. © 2013 American Cancer Society.
Malignancy risk associated with diagnostic categories defined by the Papanicolaou Society of Cytopathology pancreaticobiliary guidelines
Authors: Layfield Lester J. , Dodd Leslie , Factor Rachel , Schmidt Robert L.
Published: December 2013

BACKGROUND

Endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) is currently the predominant method for obtaining a preoperative tissue diagnosis for pancreatic lesions suspicious for malignancy. The diagnostic sensitivity and specificity of EUS‐FNA are well documented, but malignancy risk associated with the diagnostic categories proposed by the Papanicolaou Society of Cytopathology is poorly defined.

METHODS

The records of the Departments of Pathology at Duke University and the University of Utah were searched for all cases of EUS‐FNA performed for the investigation of pancreatic lesions. All cases with follow‐up surgical diagnosis or greater than 3 years of clinical follow‐up were selected. Cytologic diagnostic categories were “nondiagnostic,” “benign,” “atypical (not otherwise specified),” “suspicious for malignancy,” “neoplasm,” and “malignant.” Correlation of cytologic diagnosis with surgical and/or clinical follow‐up was made and risk of malignancy calculated for each category.

RESULTS

Three hundred seventeen EUS‐FNAs with adequate surgical or clinical follow‐up were obtained. Risk of malignancy for nondiagnostic specimens was 21%;, benign specimens, 13%; atypical cases, 74%; suspicious for malignancy, 82%; the neoplasm category, 14%; and the malignant category, 97%

CONCLUSIONS

The cytologic categories proposed by the Papanicolaou Society of Cytopathology demonstrate an increasing risk for malignancy extending from benign to malignant. Aspirates designated benign have the lowest risk of malignancy (13%) and aspirates designated malignant the highest (97%). The proposed categorization scheme stratifies risk for malignancy giving useful information to clinicians treating patients with pancreatic lesions. Cancer (Cancer Cytopathol) 2014;122:420–427. © 2013 American Cancer Society.
Water‐Soluble Ionic Palladium Complexes: Effect of Pendant Ionic Groups on Palladium Nanoparticles and Suzuki–Miyaura Reaction in Neat Water
Authors: Li Liuyi , Wu Tao , Wang Jinyun , Wang Ruihu
Published: December 2013

Three ionic nitrogen‐containing chelating ligands (L1–L3) are synthesized readily through alkylation and quaternization of 2,2′‐dipyridylamine. The charge distributions and natural bond orbital analyses of their cations are implemented by using density functional theory calculations. The catalytic performances of their water‐soluble palladium complexes are evaluated preliminarily by using the Suzuki–Miyaura cross‐coupling reaction, and high catalytic activities of aryl bromides and chlorides are achieved in neat water. The mercury drop test, poison experiments, and TEM analysis are used to demonstrate the formation of palladium nanoparticles (NPs) after the catalytic reaction. The effects of pendant ionic groups in L1–L3 on the catalytic activities and structures of the palladium NPs are disclosed. These NPs are stable in water for several weeks; they are stabilized by synergetic interactions between the chelating coordination of the 2,2′‐dipyridylamino group to the surface of the palladium NPs and the electrostatic repulsion of the ionic groups in L1–L3.
Ferric chloride‐Graphite Intercalation Compounds as Anode Materials for Li‐ion Batteries
Authors: Wang Lili , Zhu Yongchun , Guo Cong , Zhu Xiaobo , Liang Jianwen , Qian Yitai
Published: December 2013

Ferric chloride‐graphite intercalation compounds (FeCl3–GICs) with stage 1 and stage 2 structures were synthesized by reacting FeCl3 and expanded graphite (EG) in air in a stainless‐steel autoclave. As rechargeable Li‐ion batteries, these FeCl3–GICs exhibit high capacity, excellent cycling stability, and superior rate capability, which could be attributed to their unique intercalation features. This work may enable new possibilities for the fabrication of Li‐ion batteries.
Association of iron indices and type 2 diabetes: a meta‐analysis of observational studies
Authors: Orban Ester , Schwab Sigrid , Thorand Barbara , Huth Cornelia
Published: December 2013

The literature on the role of body iron status in the development of type 2 diabetes (T2D) in humans is inconsistent. We aimed to assess the association between iron indices and T2D by a meta‐analysis of previously published studies. A systematic literature search was conducted in PubMed and EMBASE. Observational studies on the association of ferritin (when controlled for age and sex), transferrin saturation, soluble transferrin receptor and transferrin with T2D were included. Pooled association estimates were calculated using a random effects model. Forty‐six eligible studies were identified. The pooled multivariable adjusted relative risks of T2D in the highest versus lowest quartile of ferritin levels were significantly elevated in both cross‐sectional as well as prospective studies and after restriction to inflammation‐adjusted studies [overall: 1.67 (95%CI 1.41‐1.99)]. The mean difference indicated 43.54 ng/mL (95%CI 28.14‐58.94) higher ferritin levels in type 2 diabetic individuals. The relative risk for a transferrin saturation ≥50% was 1.59 (95%CI 1.28‐1.97), the mean difference was −1.92% [95%CI −2.99‐(−0.85)]. Study‐specific results of soluble transferrin receptor and transferrin levels were extremely heterogeneous. Ferritin and clinically elevated transferrin saturation were strongly associated with an increased risk of T2D, overall and in prospective studies. Ferritin was also significantly associated after multivariable adjustment including inflammation. Thus, the current evidence hints at a causal effect; however, publication bias and unmeasured confounding cannot be excluded. Copyright © 2013 John Wiley & Sons, Ltd.
Evidence of constant diversification punctuated by a mass extinction in the African cycads
Authors: Yessoufou Kowiyou , Bamigboye Samuel O. , Daru Barnabas H. , van der Bank Michelle
Published: December 2013

The recent evidence that extant cycads are not living fossils triggered a renewed search for a better understanding of their evolutionary history. In this study, we investigated the evolutionary diversification history of the genusEncephalartos, a monophyletic cycad endemic to Africa. We found an antisigmoidal pattern with a plateau and punctual explosive radiation. This pattern is typical of a constant radiation with mass extinction. The rate shift that we found may therefore be a result of a rapid recolonization of niches that have been emptied owing to mass extinction. Because the explosive radiation occurred during the transition Pliocene–Pleistocene, we argued that the processes might have been climatically mediated.
Acorns containing deeper plumule survive better: how white oaks counter embryo excision by rodents
Authors: Zhang Mingming , Dong Zhong , Yi Xianfeng , Bartlow Andrew W
Published: December 2013

Several squirrel species excise the embryo of acorns of most white oak species to arrest germination for long‐term storage. However, it is not clear how these acorns counter embryo excision and survive in the arms race of coevolution. In this study, we simulated the embryo excision behavior of squirrels by removing 4 mm of cotyledon from the apical end of white oak acorns differing in embryo depths to investigate the effects of embryo excision on acorn germination and seedling performance of white oak species. The embryo depth in the cotyledons was significantly different among white oak acorns, with Quercus mongolica containing the embryo most deeply in the acorns. We found that artificial embryo excision significantly decreased acorn germination rates of Quercus variabilis, Quercus acutissima, Quercus aliena, Quercus aliena var. acutiserrata, Quercus serrata. var. brevipetiolata but not Q. mongolica. Artificial embryo excision exerted significant negative impacts on seedling performance of all oak species except Quercus aliena. Our study demonstrates the role of embryo depth of acorns in countering embryo excision by squirrels and may explain the fact that squirrels do not perform embryo excision in acorns of Q. mongolica with deeper embryos. This apparent adaptation of acorns sheds light on the coevolutionary dynamics between oaks and their seed predators.
No evidence for size‐assortative mating in the wild despite mutual mate choice in sex‐role‐reversed pipefishes
Authors: Mobley Kenyon B. , Abou Chakra Maria , Jones Adam G.
Published: December 2013

Size‐assortative mating is a nonrandom association of body size between members of mating pairs and is expected to be common in species with mutual preferences for body size. In this study, we investigated whether there is direct evidence for size‐assortative mating in two species of pipefishes,Syngnathus floridaeandS. typhle, that share the characteristics of male pregnancy, sex‐role reversal, and a polygynandrous mating system. We take advantage of microsatellite‐based “genetic‐capture” techniques to match wild‐caught females with female genotypes reconstructed from broods of pregnant males and use these data to explore patterns of size‐assortative mating in these species. We also develop a simulation model to explore how positive, negative, and antagonistic preferences of each sex for body size affect size‐assortative mating. Contrary to expectations, we were unable to find any evidence of size‐assortative mating in either species at different geographic locations or at different sampling times. Furthermore, two traits that potentially confer a fitness advantage in terms of reproductive success, female mating order and number of eggs transferred per female, do not affect pairing patterns in the wild. Results from model simulations demonstrate that strong mating preferences are unlikely to explain the observed patterns of mating in the studied populations. Our study shows that individual mating preferences, as ascertained by laboratory‐based mating trials, can be decoupled from realized patterns of mating in the wild, and therefore, field studies are also necessary to determine actual patterns of mate choice in nature. We conclude that this disconnect between preferences and assortative mating is likely due to ecological constraints and multiple mating that may limit mate choice in natural populations.
The effect of exercise on behavioural and psychological symptoms of dementia: the EVIDEM‐E randomised controlled clinical trial
Authors: Lowery David , Cerga‐Pashoja Arlinda , Iliffe Steve , Thuné‐Boyle Ingela , Griffin Mark , Lee James , Bailey Alex , Bhattacharya Rahul , Warner James
Published: December 2013

Objective

The objective of this study is to evaluate the effectiveness of a simple dyadic (person with dementia and their main carer) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia.

Method

A two arm, pragmatic, randomised, controlled, single‐blind, parallel‐group trial of a dyadic exercise regimen (individually tailored walking regimen designed to become progressively intensive and last between 20–30 min, at least five times per week).Community‐dwelling individuals with ICD‐10 confirmed dementia with the following: clinically significant behavioural and psychological symptoms, a carer willing and able to co‐participate in the exercise regimen, and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study.

Results

One hundred and thirty‐one dyads were recruited to this study. There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not (adjusted difference in means (intervention minus control) = −1.53, p = 0.6, 95% CI [−7.37, 4.32]). There was a significant between‐group difference in caregiver's burden as measured by the Zarit Caregiver Burden Inventory at week 12 (OR = 0.18, p = 0.01, CI [0.05, 0.69]) favouring the exercise group.

Conclusions

This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia, but did seem to attenuate caregiver burden. Further study to improve exercise uptake are needed. Copyright © 2013 John Wiley & Sons, Ltd.
A Comparison of Outpatient Healthcare Expenditures Between Public and Private Medical Institutions in Urban China: An Instrumental Variable Approach
Authors: Xu Judy , Liu Gordon , Deng Guoying , Li Lin , Xiong Xianjun , Basu Kisalaya
Published: December 2013

The growth of healthcare expenditure provokes constant comments and discussions, as countries battle the issues on cost containment and cost effectiveness. Prior to 1978, medical institutions in China were either state‐owned or were collective public hospitals. Since 1978, China has been trying to rebuild its healthcare system, which was destroyed during the ‘cultural revolution’, allowing private medical institutions to deliver healthcare services. As a result, private medical institutions have grown from 0% to 28.57% between 1978 and 2010. In this context, we compare outpatient healthcare expenditures between public and private medical institutions. The central problem of this comparison is that the choice of medical institution is endogenous. So we apply an instrumental variable (IV) framework utilizing geographic information (whether the closest medical institution is private) as the instrument while controlling for severity of health and other relevant confounding factors. Using China's Urban Resident Basic Medical Insurance Survey 2008–2010, we found that there is no difference in expenditure between public and private medical institutions when IV framework is used. Our econometric tests suggest that our IV model is specified appropriately. However, the ordinary least square model, which is inconsistent in the presence of endogenous regressor(s), reveals that public medical institutions are more expensive. Copyright © 2013 John Wiley & Sons, Ltd.
Value‐Based Differential Pricing: Efficient Prices for Drugs in a Global Context
Authors: Danzon Patricia , Towse Adrian , Mestre‐Ferrandiz Jorge
Published: December 2013

This paper analyzes pharmaceutical pricing between and within countries to achieve second‐best static and dynamic efficiency. We distinguish countries with and without universal insurance, because insurance undermines patients' price sensitivity, potentially leading to prices above second‐best efficient levels. In countries with universal insurance, if each payer unilaterally sets an incremental cost‐effectiveness ratio (ICER) threshold based on its citizens' willingness‐to‐pay for health; manufacturers price to that ICER threshold; and payers limit reimbursement to patients for whom a drug is cost‐effective at that price and ICER, then the resulting price levels and use within each country and price differentials across countries are roughly consistent with second‐best static and dynamic efficiency. These value‐based prices are expected to differ cross‐nationally with per capita income and be broadly consistent with Ramsey optimal prices. Countries without comprehensive insurance avoid its distorting effects on prices but also lack financial protection and affordability for the poor. Improving pricing efficiency in these self‐pay countries includes improving regulation and consumer information about product quality and enabling firms to price discriminate within and between countries. © 2013 The Authors. Health Economics published by John Wiley & Sons Ltd.
Pretreatment neutrophil‐to‐lymphocyte ratio as predictor of survival for patients with metastatic nasopharyngeal carcinoma
Authors: Jin Ying , Ye Xiao , He Chunxiao , Zhang Beibei , Zhang Yiping
Published: December 2013

Background

The outcomes of patients with metastatic nasopharyngeal carcinoma (NPC) differ between individuals. The purpose of this study was to examine the impact of neutrophil‐to‐lymphocyte ratio (NLR) on survival in patients with metastatic NPC.

Methods

A total of 229 patients with disseminated NPC were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte, and NLR on survival were examined using the proportional hazards regression model to estimate hazard ratio (HR). The relationship between short‐term treatment efficacy and pretreatment NLR was analyzed using the chi‐square test.

Results

The pretreatment elevated neutrophil count (p = .020), percentage of neutrophil (p < .001), and NLR (p = .002) were statistically significantly associated with a poor prognosis. The cutoff value selected for NLR was 3.6. The median survival time was 15.3 months for the high‐NLR group and was 23.5 months for the low‐NLR group (p < .001).

Conclusion

NLR is a prognosticator in patients with metastatic NPC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 69–75, 2015
Hepatocyte-Specific Ptpn6 Deletion Promotes Hepatic Lipid Accretion, but Reduces NAFLD in Diet-Induced Obesity: Potential Role of Pparγ
Authors: Xu Elaine , Forest Marie-Pier , Schwab Michael , Avramoglu Rita Kohen , St-Amand Emmanuelle , Caron Annabelle Z. , Bellmann Kerstin , Shum Michaël , Voisin Gregory , Paquet Marilene , Montoudis Alain , Lévy Emile , Siminovitch Katherine A. , Neel Benjamin G. , Beauchemin Nicole , Marette André
Published: December 2013

Hepatocyte-specific Shp1 knockout mice (

Ptpn6H-KO

) are protected from hepatic insulin resistance evoked by high-fat diet (HFD) feeding for 8 weeks. Unexpectedly, we report herein that

Ptpn6H-KO

mice fed an HFD for up to 16 weeks are still protected from insulin resistance, but are more prone to hepatic steatosis, as compared with their HFD-fed

Ptpn6f/f

counterparts. The livers from HFD-fed

Ptpn6H-KO

mice displayed 1) augmented lipogenesis, marked by increased expression of several hepatic genes involved in fatty acid biosynthesis, 2) elevated postprandial fatty acid uptake, and 3) significantly reduced lipid export with enhanced degradation of apolipoprotein B (ApoB). Despite more extensive hepatic steatosis, the inflammatory profile of the HFD-fed

Ptpn6H-KO

liver was similar (8 weeks) or even improved (16 weeks) as compared to their HFD-fed

Ptpn6f/f

littermates, along with reduced hepatocellular damage as revealed by serum levels of hepatic enzymes. Interestingly, comparative microarray analysis revealed a significant up-regulation of peroxisome proliferator-activated receptor gamma (

PPARγ

) gene expression, confirmed by quantitative polymerase chain reaction. Elevated PPARγ nuclear activity also was observed and found to be directly regulated by Shp1 in a cell-autonomous manner.

Conclusion :

These findings highlight a novel role for hepatocyte Shp1 in the regulation of PPARγ and hepatic lipid metabolism. Shp1 deficiency prevents the development of severe hepatic inflammation and hepatocellular damage in steatotic livers, presenting hepatocyte Shp1 as a potential novel mediator of nonalcoholic fatty liver diseases in obesity. (Hepatology 2014;59:1803–1815)
From Nef‐Isocyanide Adducts toward Functionalized 5‐Iminothiazolidines Containing Polarized CC Bonds
Authors: Yavari Issa , Pashazadeh Ramin , Hosseinpour Reza , Ghanbari Ehsan
Published: December 2013

An efficient synthesis of alkyl 5‐(alkylimino)‐3‐aryl(alkyl)‐2‐(dicyanomethylene)‐4‐hydroxythiazolidine‐4‐carboxylates, containing polarized CC bonds, via reaction of malononitrile, arylisothiocyanates, and the Nef‐isocyanide adducts, under basic conditions, is described.
PhRMA Perspective on Population and Individual Bioequivalence
Authors: Barrett Jeffrey S. , Batra Vijay , Chow Andrew , Cook Jack , Gould A. Lawrence , Heller Allen H. , Lo Man‐Wai , Patterson Scott D. , Smith Brian P. , Stritar Jeffrey A. , Vega Jose M. , Zariffa Névine
Published: December 2013

The Food and Drug Administration (FDA) issued a second‐draft guidance in August 1999 on the subject of in vivo bioequivalence, which is based on the concepts of individual and population bioequivalence (IBE and PBE, respectively). The intention of this guidance is to replace the 1992 guidance that requires that in vivo bioequivalence be demonstrated by average bioequivalence (ABE). Although the concepts of population and individual bioequivalence are intuitively reasonable, a detailed review of the literature has not uncovered clinical evidence to justify the additional burden to the innovator and generic companies as well as the consumer that the new guidelines would impose. The criteria for bioequivalence described in the draft guidance employ aggregate statistics that combine information about differences in bioavailability between formulation means and differences in bioavailability variation of formulations between and within subjects. The purely technical aspects of the statistical approach are reasonably sound. However, PhRMA believes that important operational issues remain that need to be resolved before any changes to current practice are implemented. PhRMA believes that the ideals of prescribability and switchability are intuitively reasonable, but it is uncertain of the extent to which the proposed guidance can achieve these goals. It is not clear whether the attainment of such goals is necessary in the evaluation of bioequivalence given the role this plays in drug development, and the lack of clinical evidence argues against a pressing need to change current practice. PhRMA is concerned that the trade‐off offered by the aggregate criteria may ultimately represent more harm than good to the public interest. PhRMA recommends more rigorous evaluation of methods based on two‐way crossover designs before moving to methods that require more complex designs. One such method is identified herein and contains procedures for estimating prescribability and switchability. The possibility of a phase‐in or trial period to collect replicate crossover data to further evaluate IBE and PBE and possibly allow market access based on these criteria as they are being evaluated has been proposed. PhRMA believes this is unprecedented and will offer little additional information beyond that which can be obtained by simulation or has already been collected by the FDA. Simulation studies have the advantage of allowing evaluation of the sensitivity of various procedures to represent the data patterns as created within the simulation. Operating characteristics by which proposed criteria can be adequately judged have not yet been defined. The limitations of ABE for highly variable drugs and narrow therapeutic drugs are well appreciated and may be addressed by means other than a wholesale change in the current criteria.
Single‐Dose Pharmacokinetics of Nateglinide in Subjects with Hepatic Cirrhosis
Authors: Choudhury Somesh , Hirschberg Yulia , Filipek Ronald , Lasseter Kenneth , McLeod James F.
Published: December 2013

This single‐dose, open‐label, parallel‐group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis ande matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half‐lives were comparable. Mean ± SD pharmacokinetic parameters in cirrhotic versus healthy subjects were slightly different (Cmax, 7.7 ± 4.9 vs. 5.6 ± 1.3 μg/ml; AUC(0‐t), 18.5 ± 7.5 vs. 14.2 ± 2.1 μg·h/ml, respectively). Mean apparent total clearance and mean renal clearance in both groups were comparable. Mean protein‐bound fractions were equivalent; binding appeared unaltered by metabolites. One cirrhotic and 2 healthy subjects each reported one adverse event. No statistically significant or clinically relevant alteration in pharmacokinetic parameters of nateglinide resulted from hepatic dysfunction, and it was well tolerated; therefore, adjustment of nateglinide dosage is not required in subjects with mild to moderate cirrhosis.
Linear Pharmacokinetic Behavior of Ropinirole during Multiple Dosing in Patients with Parkinson's Disease
Authors: Hubble Jean , Koller William C. , Atchison Paul , Taylor Anne C. , Citerone David R. , Zussman Barry D. , Friedman Carl J. , Hawker Noele
Published: December 2013

The objectives of this study were to measure the pharmacokinetics of ropinirole at steady state when the drug is used as an adjunct to L‐dopa and evaluate the long‐term tolerability of ropinirole in this indication. Twenty‐four pa tien ts who were taking L‐dopa for Parkinson's disease and experiencing a lack of symptomatic control were recruited. Patients received open‐label adjunctive treatment with ropinirole for up to 2 years. The starting dose was 0.5 mg bid, which could be titrated to a maximum of 6.0 mg tid. Ropinirole demonstrated approximately dose‐linear pharmacokinetics at steady state; corresponding values were higher during tid than bid dosing. A reduction in mean L‐dopa dose was maintained throughout the trial. The combination of L‐dopa and ropinirole was generally well tolerated, with only 1 patient withdrawing from treatment because of adverse events. Thus, ropinirole shows approximately linear steady‐state pharmacokinetics and a good safety profile when administered with L‐dopa.
Celecoxib Does Not Significantly Alter the Pharmacokinetics or Hypoprothrombinemic Effect of Warfarin in Healthy Subjects
Authors: Karim Aziz , Tolbert Dwain , Piergies Antoni , Hubbard Richard C. , Harper Kathleen , Wallemark Carl‐Bertil , Slater Margaret , Geis G. Steven
Published: December 2013

The objective of this study was to determine the effects of celecoxib, an anti‐inflammatory/analgesic agent that primarily inhibits COX‐2 and not COX‐1 at therapeutic doses, on the steady‐state pharmacokinetic profile and hypoprothrombinemic effect of racemic warfarin in healthy volunteers. Twenty‐four healthy adult volunteers on maintenance doses of racemic warfarin (2–5 mg daily), stabilized to prothrombin times (PT) 1.2 to 1.7 times pretreatment PT values for 3 consecutive days, were randomized to receive concomitant celecoxib (200 mg bid) or placebo for 7 days in an open‐label, multiple‐dose, randomized, placebo‐controlled, parallel‐group study of warfarin pharmacokinetics and PT. Steady‐state exposure of S‐ and R‐warfarin (area under the curve [AUC]) and maximum plasma concentration (Cmax) in subjects receiving celecoxib were within 2% to 8% of the warfarin AUC and Cmax in subjects receiving placebo during the concomitant treatment period. In addition, PT values were not significantly different in subjects receiving warfarin and celecoxib concomitantly compared with subjects receiving warfarin and placebo. In conclusion, concomitant administration of celecoxib has no significant effect on PT or steady‐state pharmacokinetics of S‐ or R‐warfarin in healthy volunteers.
Quantitative measurement of blood velocity in zebrafish with optical vector field tomography
Authors: Fieramonti Luca , Foglia Efrem A. , Malavasi Stefano , D'Andrea Cosimo , Valentini Gianluca , Cotelli Franco , Bassi Andrea
Published: December 2013

Microscopy techniques can readily visualize the finest details of embryo vasculature, but still lack to provide a complete three‐dimensional representation of blood flow parameters. We present an in‐vivo 3D imaging technique, able to reconstruct the blood cell velocity vector over a large volume of zebrafish embryos. This low cost and relatively simple technique is exploited to quantitatively assess blood velocity in the zebrafish tail at different stages of development. (© 2013 WILEY‐VCH Verlag GmbH &Co. KGaA, Weinheim)
Increased IL-6 Expression in Osteoclasts Is Necessary But Not Sufficient for the Development of Paget's Disease of Bone
Authors: Teramachi Jumpei , Zhou Hua , Subler Mark A , Kitagawa Yukiko , Galson Deborah L , Dempster David W , Windle Jolene J , Kurihara Noriyoshi , Roodman G David
Published: December 2013

Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6–/– mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), nor produce elevated levels of IL-6. We previously generated p62P394L knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2D3. Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (µQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice contributes to increased responsivity to 1,25-(OH)2D3 and increased OCL numbers, but is not sufficient to induce Paget's-like OCLs or bone lesions in vivo. © 2014 American Society for Bone and Mineral Research.
Three‐dimensional saline infusion vaginography for sonographic assessment of the anterior vaginal wall and pelvic floor descent
Authors: Rotenberg Ohad , Greston Wilma Markus , Dar Pe'er
Published: December 2013

Ultrasound has been recognized as an important tool for pelvic floor evaluation. A main limitation of the two‐dimensional transvaginal examination is in delineation of the posterior vaginal compartment and its relation to the cervix. We describe the use of three‐dimensional saline infusion vaginography as a complementary technique for the assessment of the vaginal wall and pelvic floor descent. We present several cases that demonstrate the advantages of this technique in overcoming the limitations inherent in current approaches. The improved imaging obtained by this technique enabled us to measure pelvic floor parameters and assist in evaluating pelvic floor dysfunction. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound 42:150–155, 2014
Stereospecific multiple isotopic labeling of benzyl alcohol
Authors: Roston Daniel , Kohen Amnon
Published: December 2013

Isotopically labeled enzymatic substrates and biological metabolites are useful for many mechanistic analyses, particularly the study of kinetic and equilibrium isotope effects, determining the stereospecificity of enzymes, and resolving metabolic pathways. Here, we present the one‐pot synthesis, purification, and kinetic analysis of 7R‐[2H]‐phenyl‐[14C]‐benzyl alcohol. The procedure involves a chemoenzymatic synthesis that couples formate dehydrogenase to alcohol dehydrogenase with a catalytic amount of nicotinamide cofactor. The reaction goes to completion overnight, and the measurement of a competitive kinetic isotope effect on the enzymatic oxidation of the purified product identified no 1H contamination. This measurement is very sensitive to such isotopic contamination and verified the high level of isotopic and enantiomeric purity yielded by the new synthetic procedure. Copyright © 2013 John Wiley & Sons, Ltd.
Discordance between genotypic resistance and pseudovirus phenotypic resistance in AIDS patients after long‐term antiretroviral therapy and virological failure
Authors: Yang Jing , Geng Wenqing , Zhang Min , Han Xiaoxu , Shang Hong
Published: December 2013

Sixteen original recombinant pseudoviruses were generated by cloning the reverse transcriptase and protease genes of human immunodeficiency virus (HIV)‐1 from patients into a plasmid vector (pNL4‐3‐ΔE‐EGFP). By site‐directed mutagenesis two restriction endonuclease sites, ApaI and AgeI, were inserted into pNL4‐3‐ΔE‐EGFP. Phenotypic susceptibility of recombinant pseudoviruses to five different classes of antiretroviral drugs was determined using a luciferase reporter assay system. The results were subjected to comparative analyses to detect genotype–phenotype associations. Among 16 strains tested, 12 strains had a discordant genotype–phenotype resistance pattern to at least one drug. In five strains resistance to two, in two strains to three, and in one strain resistance to four drugs was detected. HIV resistance genotyping could predict the phenotype for nevirapine and azidothymidine. For lamivudine, 2′‐3′‐didehydro‐2′‐3′dideoxythymidine and didanosine, phenotypic resistance testing was necessary. The study showed that in patients who experienced long‐term highly active antiretroviral therapy and virological failure, there is some discordance between genotypic and phenotypic HIV drug resistance. To address the issue of limited resources in China, genotypic and phenotypic resistance testing should be done for different drugs in order to guide clinical therapy more effectively.
EUROPEAN TRAINING AND RESEARCH IN PERITONEAL DIALYSIS: SCIENTIFIC OBJECTIVES, TRAINING, IMPLEMENTATION AND IMPACT OF THE PROGRAMME
Authors: Foster Tom L. , Ferrantelli Evelina , van Wier‐van der Schaaf Tanja , Beelen Robert H.J.
Published: December 2013

Background

Peritoneal dialysis (PD) offers many advantages over hospital‐based haemodialysis, including better quality of life. Despite this, there is a general under‐utilisation of PD in Europe, which, to some extent, can be attributed to a lack of knowledge and education amongst renal clinicians and nurses.

Objectives

The specific aim of the European Training and Research in Peritoneal Dialysis (EuTRiPD) programme is to address this lack of knowledge, to develop a minimum of five biomarkers that allow the prediction of outcome in PD and three therapeutic treatments to improve outcome in PD.

Approach

EuTRiPD is a EU‐wide consortium with clinical, academic and commercial partners set up to address this knowledge gap. By training through research and close collaboration between academic and commercial entities we hope to improve the outcome and uptake of PD. It is the goal of EuTRiPD to improve the currently hampered diagnostic therapeutic developments in renal replacement therapy (RRT) and structure existing high‐quality PD‐related research across Europe.

Conclusion

It is hoped that EuTRiPD can and will have a significant impact on socio‐economic and scientific aspects of PD. It is the aim for EuTRiPD to boost the uptake of PD throughout Europe by making PD the obvious choice for patients.
A refined understanding of the paleoenvironmental history recorded at the Okanagan Centre section, an MIS 4 stratotype, south‐central British Columbia, Canada
Authors: LESEMANN JEROME‐ETIENNE , BRENNAND TRACY A. , LIAN OLAV B. , SANBORN PAUL
Published: December 2013

The Okanagan Centre section is the stratotype for marine oxygen isotope stage (MIS) 4 sediments (Okanagan Centre Drift) in the southern interior of British Columbia, Canada. Previous work suggested that these sediments record two glacial and two interglacial cycles. This study reports on detailed sedimentological and geochronological investigations of lithostratigraphic units comprising the Okanagan Centre sequence, revealing successive deposition of subaqueous and subaerial outwash, a subglacial till and glaciolacustrine sediments during MIS 4. A limiting optical age of 113 ± 8 ka defines the base of this sequence. Sedimentological, paleopedological, optical dating and tephrochronological data from sediments near the middle of the sequence reveal soil development (MIS 3) in eolian sediments deposited on a river terrace overlying a deglaciated surface. Within these sediments, identification of Mt. St. Helens set C tephra suggest sedimentation between 50 and 35k 14C a BP. Optical dating corroborates the tephrochronology and suggests that this surface formed after ∼52 ± 7 ka. The record of MIS 2 glaciation is restricted to deglaciation, and overlies MIS 3 sediments above an unconformity possibly related to regional subglacial meltwater erosion. Eolian sediments containing Mt Mazama set O tephra (∼7.62k cal a BP) cap the sequence.
The clinical implications of integrating additional prognostic factors into the TNM
Authors: Henson Donald Earl. , Schwartz Arnold M. , Chen Dechang , Wu Dengyuan
Published: December 2013

Background and Objectives

The management of solid tumors is governed by host and tumor factors that traditionally have incorporated TNM staging with additional pathologic, biologic, and clinical host factors. Beyond the anatomic‐based TNM, increasingly new prognostic and predictive factors are being discovered that have important survival and treatment implications. However, because the TNM is based on a “bin” model, additional prognostic factors would rapidly overwhelm the current system. This communication demonstrates the clinical implications and improved patient prognosis derived from a new algorithmic model based on clustering analysis.

Methods

A new algorithm is described that integrates additional factors into the TNM and calculates survival.

Results

The results indicate that additional factors can be integrated into the TNM staging system providing additional patient stratification without changing the TNM definitions. Adding prognostic factors to traditional TNM staging increases substratification of given stages and identifies and separates favorable and unfavorable clinical outcomes for specific TNM stages.

Conclusion

Integration of additional prognostic factors into the TNM by a clustering algorithm can change the stratification of patient outcome. This may guide the clinician to select a more rational management program based on the additional factors and improve cohort selection for clinical trials. J. Surg. Oncol. 2014 109:391–394. © 2013 Wiley Periodicals, Inc.
Investigation of cell free BIRC5 mRNA as a serum diagnostic and prognostic biomarker for colorectal cancer
Authors: Wang Haiyan , Zhang Xin , Wang Lili , Zheng Guixi , Du Lutao , Yang Yongmei , Dong Zhaogang , Liu Yimin , Qu Ailin , Wang Chuanxin
Published: December 2013

Background

BIRC5 (Survivin), a key member of inhibitor of apoptosis family, has been shown in colorectal cancer (CRC) tumorigenesis and progress. This study investigated the expression levels of cell free BIRC5 mRNA in serum of CRC and assess its diagnostic and prognostic potential.

Methods

Levels of cell free BIRC5 mRNA were detected by reverse transcription quantitative real‐time PCR in serum of 92 CRC patients and 60 healthy volunteers.

Results

Cell free BIRC5 mRNA levels were significantly increased in serum of CRC (P < 0.001), and significantly correlated with tumor differentiation (P = 0.035), regional lymph node metastasis (P < 0.001) and TNM stage (P < 0.001). ROC curve demonstrated an optimal cut‐off value of 0.128, providing a sensitivity of 84.8% and a specificity of 80.0% for discriminating CRC from controls. The area under the ROC curve for BIRC5 mRNA was significantly larger than that for CEA (0.855 vs. 0.691, P < 0.001). Furthermore, a significantly higher diagnosis capability was showed when combined BIRC5 mRNA and CEA. High serum BIRC5 mRNA expression has a lower OS, compared with low group (36.4% vs. 73.3%, P = 0.022), and was an independent prognostic factor for CRC.

Conclusion

Serum cell free BIRC5 mRNA is a promising non‐invasive biomarker for diagnosis and prognosis of CRC. J. Surg. Oncol. 2014 109:574–579. © 2013 Wiley Periodicals, Inc.
Comparison of surgical completeness between robotic total thyroidectomy versus open thyroidectomy
Authors: Tae Kyung , Song Chang M. , Ji Yong B. , Kim Kyung R. , Kim Ji Y. , Choi Yun Y.
Published: December 2013

Objectives/Hypothesis

The aim of this study was to investigate the surgical completeness of robotic total thyroidectomy compared with conventional open thyroidectomy.

Study Design

Retrospective, case‐control study.

Methods

We studied 245 patients with papillary thyroid carcinoma who underwent total thyroidectomy and postoperative radioactive iodine (RAI) ablation. Of these, 62 patients underwent robotic thyroidectomy by a gasless unilateral axillo‐breast (GUAB) or axillary (GUA) approach, and 183 underwent conventional open thyroidectomy. We analyzed serum TSH‐stimulated thyroglobulin (Tg) and RAI uptake at the time of RAI remnant ablation to compare surgical completeness in the two groups.

Results

Tumor characteristics and complications did not differ between the two groups except TNM stage. The mean TSH‐stimulated Tg at the first RAI ablation was significantly higher in the robotic group (10.20 ± 9.98 ng/ml) than in the open group (3.85 ± 6.79 ng/ml) (P <0.001). In subgroup analysis of the robotic group by the period in which operations took place, TSH‐stimulated Tg was significantly higher than in the open group in the first (13.28 ± 11.91 ng/ml) and second (10.45 ± 9.30 ng/ml) periods, but there was no significant difference in the third period (6.00 ± 6.26 ng/ml, P = 0.141). The RAI uptake rate at the first RAI ablation did not differ between the two groups, and TSH‐stimulated Tg after RAI ablation was similar.

Conclusion

The surgical completeness of robotic total thyroidectomy by a GUAB/GUB approach is comparable to that of open thyroidectomy, if performed by experienced robotic thyroid surgeons in properly selected patients.

Level of Evidence

3b. Laryngoscope, 124:1042–1047, 2014
In Situ Reduction of Graphene Oxide in an Epoxy Resin Thermally Cured with Amine
Authors: Sangermano Marco , Tagliaferro Alberto , Foix David , Castellino Micaela , Celasco Edvige
Published: December 2013

A procedure is proposed to prepare electrically conductive epoxy resin composites exploiting in situ reduction of graphene oxide (GOx) during the epoxy thermal curing in presence of amine. The optimum curing conditions are evaluated, and the efficiency of the reduction process of GOx induced by amine is confirmed by XPS analyses. The composites electrical resistivity show a decrease by increasing filler amount, and this can only be due to the partial restoration of the conductive sp2 structure occurred during thermal curing. This is a simple, easy‐to‐scale, one‐step process to obtain electrically conductive epoxy cured materials by mixing the resin components and the well dispersible insulating GOx.
Venturing into the no‐man's land of the retina in Parkinson's disease
Authors: Bodis‐Wollner Ivan , Miri Shahnaz , Glazman Sofya
Published: December 2013

The development of optical coherence tomography (OCT) has led to increasing interest in the retina in Parkinson's disease (PD). The retina is a multilayered tissue: looking into the eye from the outside, these layers comprise the nerve fiber layer (NFL); the ganglion cell layer (GCL); the inner plexiform layer (IPL), which contains the interconnecting plexus, including tyrosine hydroxylase‐positive (dopaminergic) fibers of amacrine cells; the inner nuclear layer; and several outer retinal layers. Commercial spectral‐domain OCT has a specific program for detecting peripapillary NFL defects and a different macular program for diabetic retinopathy. Specific programs for PD are not commercially available. Taking all studies together, it seems that macular programs have a higher diagnostic yield than NFL programs, but the numbers of studies and examined patients are relatively small. It is not certain that all retinal thinning in PD is due to dopaminergic neuronal loss. When applying OCT, the where (region of interest) and the what of the focus of automated programs must be considered. With these caveats, one could take advantage of the power of OCT for looking in‐depth into the terra incognita of individual retinal layers at the fovea and perhaps at other appropriate retinal locations. © 2013 International Parkinson and Movement Disorder Society
Computational Study of Drugs by Integrating Omics Data with Kernel Methods
Authors: Wang Yongcui C. , Deng Naiyang , Chen Shilong , Wang Yong
Published: December 2013

With the rapid development of genomic and chemogenomic techniques, many omics data sources for drugs have been publicly available. These data sources illustrate drug’s biological function in the living cell from different levels and different aspects. One straightforward idea is to learn understandable rules via computational models and algorithms to mine and integrate these data sources. Here, we review our recent efforts on developing kernel‐based methods to integrate drug related omics data sources. Three promising applications of our framework are shown to predict drug targets, assign drug’s ATC‐code annotation, and reveal drug repositioning. We demonstrate that data integration does provide more information and improve the accuracy by recovering more experimentally observed target proteins, ATC‐codes, and drug repositioning. Importantly, data integration can indicate novel predictions which are supported by database search and functional annotation analysis and worthy of further experimental validation. In conclusion, kernel methods can efficiently integrate heterogeneous data sources to computationally study drugs, and will promote the further research in drug discovery in a low‐cost way.