bluuebunny/crossref_metadata_2025 huggingface dataset:
Progress in microchip enantioseparations
Authors: Nagl Stefan , Schulze Philipp , Ludwig Martin , Belder Detlev
Published: August 2009

Advances in microfluidic chips for chiral separations from 2003 to early 2009 are discussed. Microchip‐based separation techniques promise higher speed, throughput, portability, less sample and reagent consumption, better environmental compatibility, reduced cost and the prospect of system integration. Microchip electrophoresis is the most promising technique for miniaturized enantioseparations and has been performed with a variety of designs and analytes, however, other formats such as microchip electrochromatography are also gaining in popularity. Microchip fabrication, chemistry and detection issues are critically discussed and highlighted. Integration of enantioseparation techniques into multifunctional microchips are currently a rapidly advancing area of research and methods are discussed that may eventually enable enantioseparations to be the part of a holistic chemical microchip.
CE provides evidence of the stereoselective hydroxylation of norketamine in equines
Authors: Schmitz Andrea , Theurillat Regula , Lassahn Paul‐Gerhard , Mevissen Meike , Thormann Wolfgang
Published: August 2009

CE with multiple isomer sulfated‐CD as selector was used for the simultaneous analysis of the stereoisomers of ketamine, norketamine, 5,6‐dehydronorketamine and hydroxylated metabolites of norketamine in liquid/liquid extracts of (i) in vitro incubations with ketamine or norketamine and equine liver microsomes and (ii) plasma and urine of ponies receiving a target‐controlled infusion of ketamine under isoflurane anesthesia. Hydroxynorketamine metabolites with the hydroxy group at the cyclohexanone ring could be shown to be formed stereoselectively both in vitro and in vivo. Due to the lack of standard compounds, urinary extracts were fractionated by HPLC followed by characterization of the collected fractions with CE and LC‐MSn with 0.7 mmu mass discrimination. Comparison of LC‐MSn data obtained with the fractions, an in vitro microsomal sample, and both pony urine and hydrolyzed pony urine led to the identification of four hydroxylated norketamine metabolites with hydroxylation at the cyclohexanone ring, two with hydroxylation at the aromatic ring and four hydroxylated metabolites of ketamine. Due to the lower detection sensitivity, only the four hydroxynorketamine metabolites with hydroxylation at the cyclohexanone ring were observed by CE. The data suggest that demethylation of ketamine followed by hydroxylation of norketamine at the cyclohexanone ring is the major metabolic pathway in equine species and that the ketamine metabolism is highly stereoselective.
Comparative spatiotemporal analysis of fine particulate matter pollution
Authors: Pang W. , Christakos G. , Wang J‐F
Published: August 2009

The prime focus of this work is the comparative investigation, theoretical and numerical, of spatiotemporal techniques used in air pollution studies. Space‐time statistics techniques are classified on the basis of a set of criteria and the relative theoretical merits of each technique are discussed accordingly. The numerical comparison involves the applications of two representative techniques. For this purpose, the popular spatiotemporal epistemic knowledge synthesis and graphical user interface (SEKS‐GUI) software of spatiotemporal statistics is used together with a dataset of PM2.5 daily measurements obtained at monitoring stations geographically distributed over the state of North Carolina, USA. The analysis offers valuable insight concerning the choice of an appropriate spatiotemporal technique in air pollution studies. Copyright © 2009 John Wiley & Sons, Ltd.
Development of seismic fragility surfaces for reinforced concrete buildings by means of nonlinear time‐history analysis
Authors: Seyedi D. M. , Gehl P. , Douglas J. , Davenne L. , Mezher N. , Ghavamian S.
Published: August 2009

Fragility curves are generally developed using a single parameter to relate the level of shaking to the expected structural damage. The main goal of this work is to use several parameters to characterize the earthquake ground motion. The fragility curves will, therefore, become surfaces when the ground motion is represented by two parameters. To this end, the roles of various strong‐motion parameters on the induced damage in the structure are compared through nonlinear time‐history numerical calculations. A robust structural model that can be used to perform numerous nonlinear dynamic calculations, with an acceptable cost, is adopted. The developed model is based on the use of structural elements with concentrated nonlinear damage mechanics and plasticity‐type behavior. The relations between numerous ground‐motion parameters, characterizing different aspects of the shaking, and the computed damage are analyzed and discussed. Natural and synthetic accelerograms were chosen/computed based on a consideration of the magnitude‐distance ranges of design earthquakes. A complete methodology for building fragility surfaces based on the damage calculation through nonlinear numerical analysis of multi‐degree‐of‐freedom systems is proposed. The fragility surfaces are built to represent the probability that a given damage level is reached (or exceeded) for any given level of ground motion characterized by the two chosen parameters. The results show that an increase from one to two ground‐motion parameters leads to a significant reduction in the scatter in the fragility analysis and allows the uncertainties related to the effect of the second ground‐motion parameter to be accounted for within risk assessments. Copyright © 2009 John Wiley & Sons, Ltd.
Method for the reduction of in‐service instrument transformer explosions
Authors: Poljak Miroslav , Bojanić Boris
Published: August 2009

The methodology and test procedure for the reduction of possible in‐service explosions of instrument transformers to negligibly low values is described. As the introduction, an interpretation of statistical results of a survey about different types of failure in instrument transformers is given, showing that about 90% of them develop gradually, taking from several hours to several months. The International Electrotechnical Commission (IEC) is about to adopt a standardised procedure requiring that instrument transformers should withstand the effect of an internal arc. The authors are taking a critical view of the proposal; explaining its main flaws. On the basis of calculations and experimental research on models and 123 kV current transformer it is shown that the mechanism causing explosions of instrument transformers cannot be simulated well enough in the way provided for in the draft of the new IEC standard. A new concept for the reduction of explosions of instrument transformers in service called ‘explosion safe’ is proposed. It includes additional routine and special tests, and usage of devices for the detection or measurement of oil pressure rise in transformers. The proposed tests are based on the investigation ‘Volt–Time Relationships for PD Inception in Oil–Paper Insulation’. Copyright © 2009 John Wiley & Sons, Ltd.
Optimal feedback controller design for a buck converter using Gaussian type pheromone profile
Authors: Sundareswaran K. , Devi V. , Kaul Shashikant , Rajasekar N. , Palani S.
Published: August 2009

This paper reports the development of a novel optimization algorithm based on a colony of natural ants. The pheromone deposition of a group of foraging ants is perceived as a Gaussian profile and the ants are made to move by sampling the profile. The effectiveness of the algorithm is first verified on a set of benchmark functions and then extended to the design of a feedback controller for a buck converter. The proposed algorithm is illustrated through computed and measured results. Further, the new method is compared with Genetic Algorithm (GA) and is found to be on par with it. Copyright © 2009 John Wiley & Sons, Ltd.
Wavelet‐based algorithm for power quality analysis
Authors: Tse Norman C. F. , Zhou Long , Lai L. L.
Published: August 2009

This paper presents a computational algorithm for identifying integer harmonics and non‐integer harmonics by using wavelet‐based transform. The Continuous Wavelet Transform (CWT) based on the modified Complex Morlet Wavelet (CMW) is adopted to estimate harmonics present in a power waveform. A frequency detection technique is developed from the wavelet scalogram and ridges. The necessary conditions for the discrimination of adjacent frequencies, the minimum sampling frequency without aliasing and the minimum waveform length for accurate estimation of harmonics are established. Experimental works have been conducted to verify the accuracy of the proposed algorithm in estimating harmonics of power system waveforms. The proposed algorithm is comparable to Discrete Fourier Transform (DFT) in estimating stationary waveforms however the result is much better than that derived with DFT in estimating non‐stationary waveforms. Copyright © 2009 John Wiley & Sons, Ltd.
On accuracy and efficiency of constrained reinitialization
Authors: Hartmann D. , Meinke M. , Schröder W.
Published: August 2009

The reinitialization, which is required to regularize the level set function, can be computationally expensive and hence is a determining factor for the overall efficiency of a level set method. However, it often has a significantly adverse impact on the accuracy of the level set solution. This short note is meant to shed light on the efficiency and accuracy issues of the reinitialization process. Using just one clearly defined level set propagation test case with an analytical solution the solutions obtained using a recently proposed efficient lower‐order constrained reinitialization (CR) scheme and standard low‐ and high‐order reinitialization schemes are juxtaposed to evidence the superiority of the novel CR formulation. It is shown that maintaining the location of the zero level set during the reinitialization is crucial for the accuracy and that the displacement caused by standard high‐order reinitialization schemes clearly outweighs the benefit of the high‐order smoothing of the level set function. Finally, results of a three‐dimensional problem are concisely reported to demonstrate the general applicability of the CR scheme. Copyright © 2009 John Wiley & Sons, Ltd.
Efficient preconditioning techniques for finite‐element quadratic discretization arising from linearized incompressible Navier–Stokes equations
Authors: El Maliki A. , Guénette R.
Published: August 2009

We develop an efficient preconditioning techniques for the solution of large linearized stationary and non‐stationary incompressible Navier–Stokes equations. These equations are linearized by the Picard and Newton methods, and linear extrapolation schemes in the non‐stationary case. The time discretization procedure uses the Gear scheme and the second‐order Taylor–Hood element P2−P1 is used for the approximation of the velocity and the pressure. Our purpose is to develop an efficient preconditioner for saddle point systems. Our tools are the addition of stabilization (penalization) term r∇(div(·)), and the use of triangular block matrix as global preconditioner. This preconditioner involves the solution of two subsystems associated, respectively, with the velocity and the pressure and have to be solved efficiently. Furthermore, we use the P1−P2 hierarchical preconditioner recently proposed by the authors, for the block matrix associated with the velocity and an additive approach for the Schur complement approximation. Finally, several numerical examples illustrating the good performance of the preconditioning techniques are presented. Copyright © 2009 John Wiley & Sons, Ltd.
Twenty‐five years of consumer bankruptcy in continental Europe: internalizing negative externalities and humanizing justice in Denmark
Authors: Kilborn Jason J.
Published: August 2009

This paper explores the problems and processes that led to the birth of consumer bankruptcy in continental Europe, a process that began in Denmark in January 1972 and culminated with the adoption of the Danish consumer debt adjustment act, Gældssaneringslov, on 9 May 1984. While this law is often described in primarily humanitarian terms, in the sense of offering a respite to “hopelessly indebted” individuals, both the motivation for the law and its intended scope were not simply accretions on an already multi‐layered welfare system. Instead, the law was designed primarily as a pragmatic response to economically wasteful collections activities that imposed negative externalities on debtors, creditors, and especially Danish society and state coffers; the law was intended to force creditors to internalize (or eliminate) these externalities with respect to all debtors unable to pay their debts within a reasonable period of 5 years. The paper also examines the growing pains of this new system. The law originally left significant administrative discretion to judges, which produced vast disparities in treatment of cases in different regions of the country. Ultimately, a reform implemented in October 2005 made the system more accessible, more unitary throughout the country, and more humane. The effects of this reform are already visible in statistical observations of the system, though significant regional variations persist. Given the striking coincidence in timing, this paper also offers brief comparative comments on the parallel design—but very different effect—of the most significant reform of the US consumer bankruptcy law, also effective in October 2005. Copyright © 2009 John Wiley & Sons, Ltd.
Lef‐1 isoforms regulate different target genes and reduce cellular adhesion
Authors: Jesse Sarah , Koenig Alexander , Ellenrieder Volker , Menke Andre
Published: August 2009

The lymphoid enhancer factor 1 (Lef‐1) belongs to the nuclear transducers of canonical Wnt‐signalling in embryogenesis and cancer. Lef‐1 acts, in cooperation with β‐catenin, as a context‐dependent transcriptional activator or repressor, thereby influencing multiple cellular functions such as proliferation, differentiation and migration. Here we report that an increased Lef‐1 expression in human pancreatic cancer correlates with advanced tumour stages. In pancreatic tumours, two different transcripts of Lef‐1 have been detected in various stages, as demonstrated by RT‐PCR analysis. One transcript was identified as the full length Lef‐1 (Lef‐1 FL), whereas the second, shorter transcript lacked exon VI (Lef‐1 Δexon VI) compared to the published sequence. Comparative analysis of these two Lef‐1 variants revealed that they exhibit different cellular effects after transient expression in pancreatic carcinoma cells. Forced expression of Lef‐1 Δexon VI inhibited E‐cadherin expression in a β‐catenin‐independent way. Increased amounts of Lef‐1 Δexon VI resulted in reduced cellular aggregation and increased cell migration. Expression of Lef‐1 FL, but not the newly identified Lef‐1 Δexon VI, induced the expression of the cell cycle regulating proteins c‐myc and cyclin D1 in cooperation with β‐catenin and it enhanced cell proliferation. Our findings indicate that expression of alternatively spliced Lef‐1 isoforms is involved in the determination of proliferative or migratory characteristics of pancreatic carcinoma cells.
Infiltrating CD11b+CD11c+ cells have the potential to mediate inducible nitric oxide synthase‐dependent cell death in mammary carcinomas of HER‐2/neu transgenic mice
Authors: Parajuli Nirmala , Müller‐Holzner Elisabeth , Böck Günther , Werner Ernst R. , Villunger Andreas , Doppler Wolfgang
Published: August 2009

The development of autochtonous mammary tumors in HER‐2/neu transgenic mice is facilitated by immune tolerance to the neu‐transgene. However, appropriate vaccination strategies can initiate immune system‐mediated antitumor response by a process that requires IFN‐γ. We investigated the role of inducible nitric oxide synthase (iNOS) induction by IFN‐γ to promote tumor cell apoptosis. Tumors from FVBN202 mice expressing the normal neu gene under the control of the MMTV‐LTR were treated in slice cultures with IFN‐γ for up to 24 hr. Apoptosis was induced, which depended on iNOS enzymatic activity. iNOS expression was predominantly found in infiltrating CD11b+CD11c+ myeloid cells and at much lower levels in the tumor epithelium. By contrast, IFN‐γ treatment of explant cultures of tumor epithelial cells was not sufficient to efficiently induce iNOS, emphasizing an important role of the integrity of tumor tissue architecture, which was preserved in the slice cultures. This notion was further supported by the upregulation of iNOS costimulatory cytokines TNF‐α and IL‐1β in slice cultures but not in explants and the capability of purified CD11b+CD11c+ cells to enhance iNOS expression of tumor cells in cocultures. The findings suggest that tumor‐infiltrating myeloid cells in immuno‐tolerant HER‐2/neu transgenic mice possess tumor killing ability via induction of iNOS and underline the capacity of antitumor strategies designed to stimulate infiltrating myeloid cells.
Enhanced antiproliferative and proapoptotic effects on prostate cancer cells by simultaneously inhibiting androgen receptor and cAMP‐dependent protein kinase A
Authors: Desiniotis Andreas , Schäfer Georg , Klocker Helmut , Eder Iris E.
Published: August 2009

The androgen‐signaling pathway with the androgen receptor (AR) as its key molecule is widely understood to influence prostate tumor growth significantly even after androgen ablation. Under androgen‐deprived conditions, the AR may be activated inappropriately through interaction with other molecules, including cyclic AMP‐dependent protein kinase A (PKA). In a previous study, we have shown that knocking down the AR significantly inhibits prostate tumor growth. In this study, we show that combined inhibition of the AR and the regulatory subunit I alpha of PKA (RIα) with small interference RNAs significantly increased the growth‐inhibitory and proapoptotic effects of AR knockdown. This treatment strategy was effective in androgen‐sensitive and in androgen ablation‐resistant prostate cancer cells. In addition, we report that downregulating PKA RIα was sufficient to inhibit PKA signaling and interestingly also impaired AR expression and activation. Vice versa, AR knockdown induced a decline in PKA RIα, associated with reduced PKA activity. This mutual influence on expression level was specific, because siRNAs against the AR did not affect expression of PKA RIα in AR negative DU‐145 cells and a siRNA control did not affect protein expression. Another important finding of our study was that depletion of PKA RIα also potentiated the antiproliferative effect of the antiandrogen bicalutamide in androgen‐sensitive LNCaP. We therefore concluded that combined inhibition of PKA RIα and AR may be a promising new therapeutic option for prostate cancer patients and might be superior to solely preventing AR expression.
Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer
Authors: Monzon Jose G. , Cremin Carol , Armstrong Linlea , Nuk Jennifer , Young Sean , Horsman Doug E. , Garbutt Kristy , Bajdik Chris D. , Gill Sharlene
Published: August 2009

Lynch syndrome is defined by the presence of germline mutations in mismatch repair (MMR) genes. Several models have been recently devised that predict mutation carrier status (Myriad Genetics, Wijnen, Barnetson, PREMM and MMRpro models). Families at moderate‐high risk for harboring a Lynch‐associated mutation, referred to the BC Cancer Agency (BCCA) Hereditary Cancer Program (HCP), underwent mutation analysis, immunohistochemistry and/or microsatellite testing. Seventy‐two tested cases were included. Twenty‐five patients were mutation positive (34.7%) and 47 were mutation negative (65.3%). Nineteen of 43 patients who were both microsatellite stable and normal on immunohistochemistry for MLH1 and MSH2 were also genotyped for mutations in these genes; all 19 were negative for MMR gene mutations. Model‐derived probabilities of harboring a MMR gene mutation in the proband were calculated and compared to observed results. The area under the ROC curves were 0.75 (95%CI; 0.63–0.87), 0.86 (0.7–0.96), 0.89 (0.82–0.97), 0.89 (0.81–0.98) and 0.93 (0.86–0.99) for the Myriad, Barnetson, Wijnen, MMRpro and PREMM models, respectively. The Amsterdam II criteria had a sensitivity and specificity of 0.76 and 0.74, respectively, in this cohort. The PREMM model demonstrated the best performance for predicting carrier status based on the positive likelihood ratios at the >10%, >20% and >30% probability thresholds. In this referred cohort, the PREMM model had the most favorable concordance index and predictive performance for carrier status based on the positive LR. These prediction models (PREMM, MMRPro and Wijnen) may soon replace the Amsterdam II and revised Bethesda criteria as a prescreening tool for Lynch mutations.
Primary gene‐engineered neural stem/progenitor cells demonstrate tumor‐selective migration and antitumor effects in glioma
Authors: Mercapide Javier , Rappa Germana , Anzanello Fabio , King Judy , Fodstad Oystein , Lorico Aurelio
Published: August 2009

The prognosis of patients with glioblastoma multiforme (GBM) is generally poor after surgical tumor resection. With the aim of developing new adjuvant therapeutic strategies, we have investigated primary neural stem/progenitor cells (NSPC) in co‐cultures with glioma cells, and in a model of gene therapy on aggressively growing malignant glioma. NSPC exhibited tropism towards medium conditioned by glioma cells, and in adherent low‐cell density co‐culture, were attracted to, and fused with, tumor cells. Similarly, within 24–48 hr of co‐culture in suspension, NSPC‐tumor hybrids were observed, representing 2–3% of the total cell population. NSPC were then coinjected into mouse brain with GBM cells, employing NSPC expressing cyclophosphamide (CPA)‐activating enzyme cytochrome p450 2B6 (CYP2B6), which catalyzes CPA prodrug transformation into membrane diffusible DNA‐alkylating metabolites. Upon CPA administration, NSPC containing CYP2B6 elicited substantial impairment of tumor growth. When implanted intracerebrally at a distant site from the tumor, gene‐engineered NSPC specifically targeted GBM grafts, after traveling through brain parenchyma, and hindered tumor growth through local activation of CPA. Directed migration of primary NSPC corresponded closely with intracerebral and tumoral pattern of expression of vascular endothelial growth factor, which is a motility factor for NSPC. Overall, these findings indicate that therapeutic gene delivery mediated by primary NSPC is a potentially valid strategy for treatment of high‐grade gliomas.
Modulation of murine innate and acquired immune responses following in vitro exposure to electrospun blends of collagen and polydioxanone
Authors: Smith Matthew J. , Smith Donna C. , Bowlin Gary L. , White Kimber L.
Published: August 2009

In light of cell sourcing issues and the lack of a bioreactor comparable to the body, many in the field of tissue engineering have focused their efforts on designing biomaterials capable of in situ regeneration. The theory is that, by using the body as both the bioreactor and the source for cell infiltration, scaffolds composed of bioresorbable materials can be remodeled into native tissue. Thus, research into the effects of such materials on the host immune response is increasingly important. This study applies an immunotoxicological approach to evaluate the effects of electrospun blends of polydioxanone (PDO) and collagen type I on murine innate and acquired immune responses. Results indicated that these materials had few effects on innate immune responses, yet they produced significant immunomodulatory effects in multiple endpoints evaluating both branches of acquired immunity (i.e., cell‐mediated and humoral immunity). Specifically, collagen content appeared to be responsible for suppression of cell‐mediated immunity, while blends of PDO and collagen appeared to be more suppressive of antibody‐forming cell responses than either PDO or collagen alone. These results demonstrate the importance of completing evaluations into the immunotoxicological effects of biomaterials, and they suggest that such testing should become a primary focus when evaluating a material's potential foruse in tissue engineering applications. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Development and biocompatibility of a novel corrodible fluoride‐coated magnesium‐calcium alloy with improved degradation kinetics and adequate mechanical properties for cardiovascular applications
Authors: Drynda Andreas , Hassel Thomas , Hoehn René , Perz Angela , Bach Friedrich‐Wilhelm , Peuster Matthias
Published: August 2009

Recently, corrodible magnesium‐based alloys have been introduced for use as cardiovascular stents and orthopedic implants. However, rapid corrosion rates have raised questions about their biocompatibility. Therefore, we developed a binary fluoride‐coated magnesium‐calcium alloy with improved degradation kinetics. Biocompatibility of the alloys was evaluated with metabolic assays (colorimetric WST‐1 test). Furthermore, five different probes of magnesium‐calcium alloys (MgCa 0.4, 0.6, 0.8, 1.2, and 2.0 wt %) were cocultivated with human smooth muscle cells and endothelial cells. To investigate the decomposition kinetics in a physiological environment the alloys were used untreated and fluoride coated (MgF2). Mg and Ca decreased the metabolic activity in vascular cells dose‐dependently, with cytotoxic effects only at unphysiological concentrations. Uncoated magnesium alloys showed signs of decomposition after a short incubation time of 24 h in contrast to MgF2 coated alloys. After 10 days smooth muscle and endothelial cells around the alloys were still alive, whereas colonization of the surfaces was only observed for smooth muscle cells. The fluoride‐coated MgCa alloys exhibited good results concerning mechanical properties, degradation kinetics, and biocompatibility in vitro. We conclude that a binary fluoride magnesium‐calcium alloy is a promising candidate for the production of cardiovascular stents. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Leptin attenuates hypoxia/reoxygenation‐induced activation of the intrinsic pathway of apoptosis in rat H9c2 cells
Authors: Shin Eyun‐Jung , Schram Kristin , Zheng Xi‐long , Sweeney Gary
Published: August 2009

Cardiomyocyte apoptosis is a component of cardiac remodeling that can contribute to heart failure in obesity. A role for leptin in mediating this process has been suggested and the objective of this work was to investigate the effect of leptin on apoptosis and associated mechanisms in H9c2 cells which were subjected to hypoxia/reoxygenation (HR) to mimic myocardial ischemia/reperfusion. Qualitative immunofluorescent and quantitative laser scanning cytometry approaches demonstrated that exposure of cells to HR increased DNA fragmentation (TUNEL staining) which was attenuated by leptin (6 nM, 1 h) pretreatment. We also found increased annexin‐V binding and caspase‐3 activity in cells exposed to HR, both of which were attenuated by leptin pretreatment. Leptin reduced HR‐induced translocation of the pro‐apoptotic protein Bax to the mitochondrial membrane, which provides a mechanism to explain its protective effect. Consequently, leptin attenuated the HR‐induced decrease in mitochondrial membrane potential and increase in cytochrome c release from mitochondria. Leptin treatment increased the phosphorylation of p38 MAPK and AMPK and respective inhibitors of these kinases, SB203580 and Compound C, prevented the ability of leptin to decrease HR‐induced caspase‐3 activity. In conclusion, we establish mechanisms via which leptin exerts anti‐apoptotic effects that may be of significance in understanding the development of heart failure in obesity. J. Cell. Physiol. 221: 490–497, 2009. © 2009 Wiley‐Liss, Inc.
Growth inhibition of bovine pulmonary artery smooth muscle cells following long‐term heparin treatment
Authors: Mrabat Hicham , Garg Hari G. , Hales Charles A.
Published: August 2009

Heparin (HP) inhibits pulmonary artery smooth muscle cell (PASMC) growth in vitro and vascular remodeling in vivo. Bârzu et al. (1994) suggested that the antiproliferative effect of HP on rat aortic smooth muscle cell in vitro diminishes with prolonged exposure to heparin. We exposed cultured bovine PASMC (BPASMC) to prolonged pretreatment with 20 µg/ml of 0‐hexanoylated HP from passages 3 to13 and compared them to control (no pretreatment) cultures of identical passages. The pretreated BPASMC and control groups were growth arrested for 48 h, followed by treatment of 0‐hexanoylated HP at different doses. On day 5, the growth inhibition of BPASMC was determined. The percent inhibition by 1 µg/ml of 0‐hexanoylated HP was 46 ± 14% versus 62 ± 13%, for control and pretreated BPASMC, respectively. At 10 µg/ml the inhibition was 62 ± 7% versus 84 ± 6%. For 100 µg/ml the inhibition increased to 92 ± 5% versus 100% and at 200 µg/ml the inhibition was 95 ± 3% versus 100%. BPASMC (with or without preexposure to 0‐hexanoylated HP), at passage 13, were sensitive to the growth inhibitory effect of 0‐hexanoylated HP with no significant difference among the groups (95 ± 3% inhibition vs. 100% for pretreated BPASMC). We found that 0‐hexanoylated HP‐induced necrosis as shown by flow cytometry and only minor apoptosis. Caspase‐3 and PARP detection was insignificant between the groups. In summary, no cell subpopulation at long‐term treatment exhibited resistance to 0‐hexanoylated HP. The HP antiproliferative effect on SMC is potentially important in defining new approaches to the treatment of the remodeled vasculature of pulmonary hypertension. J. Cell. Physiol. 221: 603–608, 2009. © 2009 Wiley‐Liss, Inc.
Immobilized HIV‐1 Tat protein promotes gene transfer via a transactivation‐independent mechanism which requires binding of Tat to viral particles
Authors: Nappi Filomena , Chiozzini Chiara , Bordignon Valentina , Borsetti Alessandra , Bellino Stefania , Cippitelli Marco , Barillari Giovanni , Caputo Antonella , Tyagi Mudit , Giacca Mauro , Ensoli Barbara
Published: August 2009

Background

Retroviral transduction of cells is improved upon virus adsorption onto immobilized fibronectin (FN) fragments. Because HIV‐1 Tat possesses the same functional domains that lead to increased transduction efficiency in FN by colocalization of bound virus and cells, we hypothesized that Tat could enhance gene transfer by a similar mechanism.

Methods

Single‐cycle replication retro‐ or lentivirus carrying green fluorescent protein or cloramphenicol acetyltransferase as reporter genes were added to wells coated with Tat or Tat peptides. Wells were extensively washed to remove unbound virus and levels of transduction were detected by measuring reporter gene expression. Virus adsorption to immobilized Tat was measured using a p24 antigen capture assay.

Results

Immobilized Tat efficiently binds retro‐ and lentiviral particles and mediates virus transmission at virus input doses that were otherwise unable to transduce susceptible cells. Virus adsorption to Tat is not mediated by envelope glycoprotein (Env) because immobilized Tat binds and retains vesicular stomatitis virus G (VSV‐G) pseudotypes as well as envelope‐free particles. HIV‐1 Env or VSV‐G are required for Tat‐assisted transduction, which is abrogated by an antibody blocking the HIV‐1 Env–CD4 interaction. Tat‐assisted transduction is mediated by the cysteine‐rich region of Tat, which is known to be essential for Tat transactivation activity. However, Tat transactivation is not required for Tat‐assisted transduction, as indicated by the enhancement of transduction by transactivation‐silent Tat mutants.

Conclusions

Immobilized Tat promotes virus transduction by a transactiva‐ tion‐independent mechanism, which requires binding of virus to Tat. Recombinant Tat or Tat fragments provide a new method to increase efficiency of retro‐ and lentiviral based gene transfer and gene therapy. Copyright © 2009 John Wiley & Sons, Ltd.
Afraid in the hospital: Parental concern for errors during a child's hospitalization
Authors: Tarini Beth A. , Lozano Paula , Christakis Dimitri A.
Published: August 2009

OBJECTIVE:

(1) To determine the proportion of parents concerned about medical errors during a child's hospitalization; and (2) the association between this concern and parental self‐efficacy with physician interactions.

STUDY DESIGN:

Cross‐sectional survey.

SETTING:

Tertiary care children's hospital.

PARTICIPANTS:

Parents of children admitted to the general medical service.

OUTCOME MEASURE:

Parental concern about medical errors.

METHODS:

Parents were asked their agreement with the statement “When my child is in the hospital I feel that I have to watch over the care that he/she is receiving to make sure that mistakes aren't made.” We used multivariate logistic regression to examine the association between parents' self‐efficacy with physician interactions and the need “to watch over a child's care,” adjusting for parent and child demographics, English proficiency, past hospitalization, and social desirability bias.

RESULTS:

Of 278 eligible parents, 130 completed surveys and 63% reported the need to watch over their child's care to ensure that mistakes were not made. Parents with greater self‐efficacy with physician interactions were less likely to report this need (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.72‐0.92). All parents who were “very uncomfortable” communicating with doctors in English reported the need to watch over their child's care to prevent mistakes.

CONCLUSIONS:

Nearly two‐thirds of surveyed parents felt the need to watch over their child's hospital care to prevent mistakes. Parents with greater self‐efficacy with physician interactions were less likely to report the need to watch over their child's care while parents with lower English proficiency were more likely to report this need. Journal of Hospital Medicine 2009;4:521–527. © 2009 Society of Hospital Medicine.
Synthesis of [13C4]Baraclude® (entecavir)
Authors: Tran Scott B. , Ekhato Ihoezo V. , Rinehart J. Kent
Published: August 2009

Entecavir, labeled as 1H‐[13C4]purin‐6(9H)‐one, was prepared from commercially available [13C]guanidine HCl, 1 and diethyl [1,2,3‐13C3]malonate, 2. The reagents were condensed together to give 2‐amino‐4,6‐dichloro[2,4,5,6‐13C4]pyrimidine 3, which in turn was coupled to an optically active amino cyclopentanol derivative, 9. A further sequence of eight reaction steps completed the constructions of the purine ring system and the exocyclic olefin attachment on the cyclic pentyl portion, 18. The removal of the methoxide and benzyl protecting groups gave [13C4]entecavir, 20 in an overall yield of 6.8%. The chemical purity of the title compound was determined by HPLC to be 99.23%. The percent isotopic [13C4] abundance was found by mass spectral analysis to be 96.7%. No detectable level of the unlabeled entecavir was found by LC‐MS analysis. Copyright © 2009 John Wiley & Sons, Ltd.
Lack of prognostic significance of serum DNA methylation of DAPK, MGMT, and GSTPI in patients with non‐small cell lung cancer
Authors: Hoffmann A.C. , Kaifi J.T. , Vallböhmer D. , Yekebas E. , Grimminger P. , Leers J.M. , Izbicki J.R. , Hölscher A.H. , Schneider P.M. , Metzger R. , Brabender J.
Published: August 2009

Background and Objectives

To further improve the screening, diagnosis and therapy of patients with non‐small cell lung cancer (NSCLC) additional diagnostic tools are desperately warranted. Aim of this study was to investigate the potential of the DNA methylation of DAPK, MGMT, and GSTPI in serum of patients with NSCLC as a prognostic molecular marker in this disease.

Methods

Seventy‐six patients with NSCLC were included in this study. The analysis of DNA methylation in serum of patients was performed on pre‐operative samples. Following DNA isolation and bisulfite‐treatment, DNA methylation was analyzed by quantitative‐methylation‐specific real‐time PCR with β‐actin as the internal reference gene.

Results

DNA methylation was detectable with following frequencies: DAPK 68.4%, MGMT 7.9%, GSTPI 0%. There were no associations between DNA methylation status and histology, tumor stage, grading or gender detectable. With a mean follow‐up of 19.7 months the median survival was 26.3 months. There were no associations between the status of DNA methylation in patient's serum and prognosis detectable.

Conclusion

The analysis of DNA methylation in serum of patients with NSCLC by quantitative‐methylation‐specific real‐time PCR is technically feasible. Although our results suggest quantification of DNA methylation in serum not of prognostic significance in this disease, further studies are warranted to determine the future potential of this molecular approach. J. Surg. Oncol. 2009;100:414–417. © 2009 Wiley‐Liss, Inc.
Short length of stay and rapid recovery to normal function after surgery for metastatic melanoma to abdominal and retroperitoneal viscera
Authors: Dengel Lynn T. , Slingluff Jr. Craig L.
Published: August 2009

Background

Metastatic melanoma to abdominal and retroperitoneal viscera carries a poor prognosis possibly resulting in reluctance to offer surgical management. There is value in defining the morbidity of such surgery.

Methods

Review of a prospectively maintained database identified patients with metastatic melanoma to abdominal or retroperitoneal viscera who underwent surgery from 9/99 to 8/06.

Results

Nineteen patients underwent surgery for metastasis to abdominal or retroperitoneal viscera detected by clinical symptoms (80%), or imaging (20%). The median length of stay was 7 days. There was no perioperative mortality. Surgical complications occurred in four patients. At initial follow‐up, 13 patients (68%) had returned to baseline function, 7 of which reported improvement. Four patients (21%) had minimal symptoms, and only two patients (11%) had significantly limited function. Median follow‐up was 35 months, at which time 9 of the 19 patients (47%) were still alive, with 3‐ and 5‐year Kaplan–Meier survival estimates of 53% (SE 12) and 45% (SE 12), respectively, and 2 of the 19 patients are alive at over 8 years since surgery.

Conclusion

In selected cases, surgery may have both palliative benefit and curative potential for patients with visceral metastases of melanoma. Surgical management of such patients should be encouraged in appropriate clinical settings. J. Surg. Oncol. 2009;100:481–483. © 2009 Wiley‐Liss, Inc.
Clinical and histopathological features of remnant gastric cancers, after gastrectomy for synchronous multiple gastric cancers
Authors: Fujita Takeo , Gotohda Naoto , Takahashi Shinichiro , Nakagohri Toshio , Konishi Masaru , Kinoshita Taira
Published: August 2009

Background

Remnant gastric cancers have been extensively investigated; however, little has been unveiled the features of remnant gastric cancers with regard to the existence of synchronous multiple lesions. We evaluated the clinicopathological features of remnant gastric cancers, after initial gastrectomy for both single and multiple gastric cancers.

Methods

We retrospectively analyzed 3,042 patients diagnosed with gastric cancers who underwent gastrectomy. Of these, total gastrectomy cases were excluded, and remaining 2,120 cases were investigated.

Results

Among the 2,120 patients, 1,967 patients were histopathologically diagnosed with solitary lesion and 153 patients with multiple lesions. The incidence of remnant gastric cancers was higher in patients with multiple lesions at initial surgery than those with solitary lesion (P < 0.05). Moreover, remnant cancers developed within shorter duration of follow‐up after treatment of synchronous multiple lesions compared to those that developed after treatment of solitary lesions (P = 0.05). Among the patients treated for synchronous multiple lesions, distance from the oral margin was a potential risk factor for the development of secondary cancers in the remnant stomach.

Conclusions

Patients with synchronous multiple gastric cancers are more susceptible to the development of secondary cancers in their remnant stomach. These patients need careful follow‐up after initial gastrectomy. J. Surg. Oncol. 2009;100:466–471. © 2009 Wiley‐Liss, Inc.
Quantitative analysis of Survivin RNA expression in blood as a non‐invasive predictor of response to neoadjuvant radiochemotherapy in esophageal cancer
Authors: Grimminger Peter , Vallböhmer Daniel , Hoffmann Andreas , Schulte Christian , Bollschweiler Elfriede , Schneider Paul M. , Hölscher Arnulf H. , Metzger Ralf , Brabender Jan
Published: August 2009

Background and Objectives

Analysis of survivin RNA expression in peripheral blood as a non‐invasive molecular predictor of response to neoadjuvant radiochemotherapy in patients with locally advanced cancer of the esophagus.

Material and Methods

Blood samples were drawn from 29 patients with esophageal cancer prior to neoadjuvant radiochemotherapy. After extraction of cellular tumor‐RNA from blood samples, quantitative expression analysis of survivin was done by quantitative real‐time RT‐PCR.

Results

Twenty of 29 (69%) of patients showed a minor histopathological response and 9 of 29 (31%) showed a major‐response to neadjuvant radiochemotherapy. RNA expression in blood of patients was detectable for survivin in 27.6%, and in 100% for β‐actin. The mean survivin expression was not significantly different between minor‐ and major‐responders. No significant associations were detected between survivin expression levels and patients clinical variables. A high expression level for survivin was significantly associated with a minor‐response to neoadjuvant treatment (P = 0.042). Relative survivin expression levels above 0.15 were not associated with major histopathological response (sensitivity: 35%; specificity: 100%).

Conclusion

Minor‐response to the applied therapy was significantly associated with a high survivin RNA expression level in patient's blood. Survivin appears to be a specific non‐invasive predictor of response to neoadjuvant therapy in esophageal cancer. J. Surg. Oncol. 2009;100:447–451. © 2009 Wiley‐Liss, Inc.
Gastrinomas: A historical perspective
Authors: Yeung Meei J. , Pasieka Janice L.
Published: August 2009

The journey of gastrinomas had its beginnings in 1955 when Zollinger and Ellison published their seminal paper (Zollinger and Ellison, Ann Surg 1955; 142: 709–723). The evolution of the diagnosis and management of this syndrome has paralleled many important advances in medicine, including the development of various diagnostic tools to the major impact of medical treatment on the management of an inherently surgical pathology. There are numerous excellent review articles on the most current developments and treatment options of gastrinomas available in the literature today. The purpose of this paper is to present a historical perspective on this most fascinating condition. This article will illustrate the way in which the discovery of gastrinomas evolved and how its management has developed with it. The evolution of the surgical treatment of gastrinomas has evolved over the last 50 years. J. Surg. Oncol. 2009;100:425–433. © 2009 Wiley‐Liss, Inc.
A retrospective comparison of clinical outcomes and quality of life measures between definitive chemoradiation alone and radical surgery for clinical stage II–III esophageal carcinoma
Authors: Yamashita Hideomi , Okuma Kae , Seto Yasuyuki , Mori Kazuhiko , Kobayashi Shino , Wakui Reiko , Ohtomo Kuni , Nakagawa Keiichi
Published: August 2009

Background

This retrospective study was conducted to compare the treatment and quality of life (QOL) results between radical surgery and definitive chemoradiotherapy (CRT) for stage II–III carcinoma of the esophagus.

Methods

Between 2000 and 2009, 128 consecutive patients were selected for this study in which 72 were treated with definitive CRT and 56 with radical surgery. QOL was assessed using Functional Assessment of Cancer Therapy‐Esophagus for 51 patients who were free of disease at the time of survey.

Results

With a median follow‐up period of 37.8 months with 66 survivors, the 4y‐DFS in the surgery group were 36% in the CRT group and 51% in the surgery group (P = 0.0028). In the CRT group, the number of cases of the advanced age, T4 stage, and stage III was significantly larger than the surgery group. QOL assessments were completed at rates of 100% in the CRT group and 88% in the surgery group. Overall E Total score had a significant difference between arms (CRT > surgery, P = 0.045).

Conclusions

CRT was inferior to surgery in survival but superior in QOL measures, although the CRT group had a larger number of patients with poorer prognostic factors. J. Surg. Oncol. 2009;100:435–441. © 2009 Wiley‐Liss, Inc.
Prognostic significance of immunohistochemically detected lymph node micrometastases in pT0N0 esophageal squamous cell carcinoma
Authors: Chao Yin‐Kai , Yeh Chi‐Ju , Chuang Wen‐Yu , Fan Kang‐Hsing , Hsieh Ming‐Ju , Chu Yen , Cheng Ann‐Joy , Liu Hui‐Ping
Published: August 2009

Background

Pathological complete response (pCR) after chemoradiotherapy (CRT) is the best predictor of survival in patients with squamous cell carcinoma (SCC) of the esophagus. Although no adjuvant treatment is recommended for individuals who achieve pCR, approximately 30% of these patients develop a recurrence. We applied an immunohistochemistry (IHC) stain on resected lymph nodes to evaluate the incidence of lymph node micrometastases (LNMs) and its prognostic significance.

Methods

Between 1995 and 2004, paraffin‐embedded specimens for evaluating the presence of LNM were available for 52 pCR patients. We performed IHC staining with the cytokeratin antibody AE1/AE3 on resected lymph nodes and correlated the pathological findings to cancer recurrence and survival.

Results

A total of 510 lymph nodes from 52 patients were examined. The incidence of LNM in pathological complete responders after CRT was 11.5%. Only six patients were found to have AE1/AE3‐positive cells in the IHC staining. However, patients with LNM had a higher recurrence rate (50% vs. 22%, P = 0.16) and a reduced disease‐free survival rate (44% vs. 75%, P = 0.16). Patients with LNM had a 3.6‐fold higher probability to develop recurrence compared with those without LNM (P = 0.15).

Conclusion

LNMs are uncommon in pathological complete responders but hold prognostic significance. J. Surg. Oncol. 2009;100:559–562. © 2009 Wiley‐Liss, Inc.
The value of anatomical liver sectionectomy for patients with a solitary hepatocellular carcinoma from 2 to 5 cm in greatest diameter
Authors: Yamamoto Masakazu , Ariizumi Shun‐ichi , Katagiri Satoshi , Kotera Yoshihito , Takahashi Yutaka
Published: August 2009

Background

The value of anatomical liver sectionectomy for patients with a solitary hepatocellular carcinoma (HCC) from 2 to 5 cm in greatest diameter has not been clarified.

Methods

We retrospectively studied 454 patients with a solitary HCC from 2 to 5 cm in greatest diameter who underwent initial curative hepatectomy from 1991 to 2006. We separated the liver into three segments according to the Glissonean pedicle ramification (Takasaki's liver segments). Takasaki's segment is recognized as a section in the International Hepato‐Pancreato‐Biliary Association Brisbane 2000 terminology. Outcomes after sectionectomy (n = 143) and partial sectionectomy (n = 311) for patients with a solitary HCC from 2 to 5 cm in greatest diameter were examined.

Results

The 5‐year recurrence‐free survival rate and survival rate after sectionectomy (42% and 81%, respectively) were significantly better than those after partial sectionectomy (27%: P = 0.0023, and 66%: P = 0.0006, respectively). Multivariate analysis showed sectionectomy to be a significant independent prognostic factor for recurrence‐free survival and overall survival in patients with a solitary HCC from 2 to 5 cm in greatest diameter (P = 0.0217, and P = 0.0085, respectively).

Conclusions

Anatomical liver sectionectomy prevents intrahepatic recurrence of HCC and prolongs survival in patients with a solitary HCC from 2 to 5 cm. J. Surg. Oncol. 2009;100:585–588. © 2009 Wiley‐Liss, Inc.