bluuebunny/crossref_metadata_2025 huggingface dataset:
Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors
Authors: Krasin Matthew J. , Davidoff Andrew M. , Rodriguez‐Galindo Carlos , Billups Catherine A. , Fuller Christine E. , Neel Michael D. , Merchant Thomas E.
Published: June 2005

BACKGROUND

The local management of Ewing sarcoma family of tumors (ESFT) often centers on the surgical resectability of the primary lesion and physician biases regarding differences in the morbidity between primary surgical and radiotherapeutic management.

METHODS

The authors retrospectively reviewed the records of 33 patients with localized ESFT who underwent surgery and received systemic chemotherapy at St. Jude Children's Research Hospital (Memphis, TN). Two multiagent systemic chemotherapy regimens were used: 14 patients received vincristine, doxorubicin, cyclophosphamide, and actinomycin D (VACA), and 19 received VACA in combination with ifosphamide and etoposide. The primary tumor was surgically resected via a wide, local excision (n = 32) or a marginal excision (n = 1)performed either at diagnosis or after 3–5 months of systemic chemotherapy. Clinical outcome and prognostic factors for disease control were reported in the current study.

RESULTS

The median follow‐up for patients was 9.9 years. The 5‐year and 10‐year survival rates were 84.5% and 75.8%, respectively. At 5 years, the cumulative incidence of local disease recurrence was 12.5%, and the event‐free survival (EFS) rate was 71.7%. The same values were found at 10 years. The site of tumor origin was a significant predictor of EFS. The survival rate of patients whose tumors arose in bone was 78.6%, and the survival rate of patients whose tumors originated in soft tissue was 25.0% (P = 0.028). No other factors investigated were predictive of outcome.

CONCLUSIONS

Local disease control and overall outcome for patients with ESFT managed by multiagent systemic therapy and surgery was excellent. Local disease control rates remained near 90% at 10‐year follow‐up. Patients with extraosseous primary sites of disease may fare less well with this approach to therapy. Cancer 2005. © 2005 American Cancer Society.
Screening and preventive behaviors one year after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma
Authors: Collins Veronica , Meiser Bettina , Gaff Clara , St. John D. James B. , Halliday Jane
Published: June 2005

BACKGROUND

Prevention benefits from predictive genetic testing for cancer will only be fully realized if appropriate screening is adopted after testing. The current study assessed screening and preventive behaviors during 12 months after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma (HNPCC) in an Australian clinical cohort.

METHODS

Participants received predictive genetic testing for HNPCC at one of five Australian familial cancer clinics. Data on self‐reported screening behaviors (colonoscopy, and endometrial sampling and transvaginal ultrasound for women) and prophylactic surgery (colectomy, and hysterectomy and bilateral oophorectomy for women) were collected using postal questionnaires before (baseline) and 12 months after receipt of genetic test results. Age, gender, perceived risk of cancer, and cancer‐specific distress were assessed as predictors of colonoscopic screening.

RESULTS

In the current study, 114 participants returned baseline questionnaires (32 carriers and 82 noncarriers of an HNPCC mutation). Ninety‐eight participants also returned a 12‐month follow‐up questionnaire. Of those ≥ 25 years, 73% reported having had a colonoscopy before genetic testing. At follow‐up, 71% (15 of 25) of carriers and 12% (8 of 65) of noncarriers reported having a colonoscopy in the 12 months after receipt of test results. The reduction in colonoscopy among noncarriers was statistically significant (P < 0.001). High perceived risk was associated with colonoscopy at baseline. At follow‐up, mutation status was the only variable significantly associated with colonoscopy. Among female mutation carriers, 47% reported having transvaginal ultrasonography and 53% endometrial sampling during follow‐up. There was low uptake of prophylactic surgery for colorectal, endometrial, or ovarian carcinomas.

CONCLUSIONS

The majority of individuals reported appropriate screening behaviors after predictive genetic testing for HNPCC. The small group of noncarriers who had screening after genetic testing might benefit from additional counseling. Cancer 2005. © 2005 American Cancer Society.
Texture Effects of Circularly Ordered Fibers
Authors: Marlow Frank , Kleitz Freddy , Wilczok Ursula , Schmidt Wolfgang , Leike Ines
Published: June 2005

Powder samples can show pronounced texture effects in X‐ray scattering. Here, texture effects are described theoretically for circularly ordered fibers and shown experimentally for a special type of these fibers based on nanostructured silica. The systematic diffraction peak intensity dependences, observed with the tilting of the samples, fit well with the theoretical model proposed and can be used as an efficient detection method for circulite‐type mesopore organization. Our investigations clearly emphasize the difficulties encountered in the interpretation of peak intensities in the X‐ray scattering analyses because of pronounced texture effects.
Voltammetric Sizing of Inert Particles
Authors: Davies Trevor J. , Lowe Eleanor R. , Wilkins Shelley J. , Compton Richard G.
Published: June 2005

The average size of inert particles is determined using a simple electrochemical procedure. Alumina particles are deposited on an edge‐plane graphite electrode, and a cyclic voltammogram is recorded. The scan rate employed varies between 0.2 and 2 V s−1. At these scan rates the diffusion layer thickness is greater than the size of the alumina particles, minimizing the influence of the particles′ height on the observed voltammetry. The average size of the particles is determined via comparison of the experimental voltammograms with simulations.
Solvent‐Mediated Redox Transformations of Ytterbium Bis(indenyl)diazabutadiene Complexes
Authors: Trifonov Alexander A. , Fedorova Elena A. , Ikorskii Vladimir N. , Dechert Sebastian , Schumann Herbert , Bochkarev Mikhail N.
Published: June 2005

The reactions of diamagnetic [(C9H7)2Yb(THF)2] (2) and [rac‐(CH2‐1‐C9H6)2Yb(THF)2] (3) with tBuN=CH–CH=NtBu (DAD) in toluene result in the formation of the paramagnetic complexes [(C9H7)2Yb(DAD)] (4) and [rac‐(CH2‐1‐C9H6)2Yb(DAD)] (5), respectively. The IR, UV/Vis, and 1H NMR spectroscopic data, the magnetic properties, and the single‐crystal X‐ray diffraction studies of 4 and 5 indicate that in the solid state and in noncoordinating media both complexes are ytterbium(III) derivatives containing the DAD radical‐anion, whereas the 1H NMR and UV/Vis spectra of solutions of 4 and 5 in the coordinating solvent THF give evidence for divalent ytterbium. Recrystallization of 4 and 5 from THF/hexane results in the recovery of the starting ytterbium complexes 2 and 3 due to an unusual redox substitution of the radical anion of diazabutadiene by THF in the coordination sphere of ytterbium. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Anion Template Effect and the Polymerization Degree – Diversity through Flexibility
Authors: Nättinen Kalle I. , de Bairos Paulo E. N. , Seppälä Petri J. , Rissanen Kari T.
Published: June 2005

Two 2D (M1 and M2) and one 1D (M3) metal‐organic frameworks (MOFs) have been prepared from pyridine functionalized tetradentate ligand tetrakis(nicotinoxymethyl)methane TNM with silver tetrafluoroborate, nickel chloride, and copper hexafluorophosphate. M1 manifests a previously unpresented mode of 4,4 threefold parallel interpenetration for 2D MOFs. Large channels (vdW diameter 9.4 Å) through eclipsed 2D layers of M2 were observed. While the open space percentage in the noninterpenetrated M2 was 38.0 %, the triple interpenetration of the sheets of M1 reduced the void to 10.8 %. With the same ligand and a similar, weakly coordinating anion as that in M1, the structure M3 was rendered one‐dimensional. The result is explained partly by the flexibility of the TNM ligand and partly by the lack of a suitable bridging solvent. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Reactions of Zirconocene Bis(trimethylsilyl)acetylene Complexes with Fluorinated Pyridines: C–H vs. C–F Bond Activation
Authors: Jäger‐Fiedler Ulrike , Arndt Perdita , Baumann Wolfgang , Spannenberg Anke , Burlakov Vladimir V. , Rosenthal Uwe
Published: June 2005

The zirconocene complexes Cp2Zr(L)(η2‐Me3SiC2SiMe3) (1a: L = THF; 1b: L = pyridine) and the ethylene bis(tetrahydroindenyl) complex rac‐(ebthi)Zr(η2‐Me3SiC2SiMe3) (2) react with 2,3,5,6‐tetrafluoropyridine with C–H bond activation to produce the 4‐substituted pyridyl complexes with agostic alkenyl groups Cp'2Zr(4‐C5NF4)[–C(SiMe3)=CH(SiMe3)] (Cp'2 = Cp2) (3) and (Cp'2 = ebthi) (4). With 2,3,4,6‐tetrafluoropyridine, after C–H bond activation, complex 2 yields two isomers of the 5‐substituted pyridyl complex rac‐(ebthi)Zr(3‐C5NF4)[–C(SiMe3)=CH(SiMe3)] with agostic alkenyl groups, 5a and 5b. With pentafluoropyridine complex 1b gives, after dissociation of the bis(trimethylsilyl)acetylene (btmsa), C–F bond activation at the 4‐position and formation of Cp2Zr(4‐C5NF4)F (6). Complex 1b reacts with 3‐chloro‐2,4,5,6‐tetrafluoropyridine by means of a preferred C–Cl activation to give Cp2Zr(3‐C5NF4)Cl (7). These results are in contrast to the reactions of the titanium complex Cp2Ti(η2‐Me3SiC2SiMe3) which, with 2,3,5,6‐tetrafluoropyridine, gaveC–F activation in preference to C–H activation. With pentafluoropyridine, C–F bond activation at the 2‐position was found rather than at the 4‐position. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
One‐Step Synthesis of Symmetrically Substituted 2,6‐Bis(pyrazol‐1‐yl)pyridine Systems
Authors: Zoppellaro Giorgio , Baumgarten Martin
Published: June 2005

A one‐pot synthetic route that allows functionalization of the 2,6‐bis(pyrazol‐1‐yl)pyridine backbone in the 4‐ and 4″‐pyrazole positions by direct H(4)‐pyrazole halogen exchange is described. The diiodo derivative in particular provides easy access to additional functionalities through both Sonogashira and Grignard exchange reactions. These synthons represent optimal building blocks for the extension of the chelating core and for the assembly of rigid organic and metalloorganic nanostructures. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Structures, Spectral and Electrochemical Properties ofN‐(Naphth‐2‐ylmethyl)‐Appended Porphyrinogens
Authors: Hill Jonathan P. , Schmitt Wolfgang , McCarty Amy Lea , Ariga Katsuhiko , D’Souza Francis
Published: June 2005

Alkylation of 5,10,15,20‐tetrakis(3,5‐di‐tert‐butyl‐4‐oxo‐2,5‐cyclohexadienylidene)porphyrinogen at its macrocyclic nitrogen atoms results in four multiplyN‐substituted products, which were isolated and characterized. The electrochemical and spectroelectrochemical properties of these compounds were determined. Molecular structures of theN‐alkylated compounds are influenced strongly by intermolecular π‐π stacking interaction between naphthyl groups leading to formation of dimers or stacked arrays of the macrocycle depending on multiplicity of substituents. The redox and spectral properties of the compounds are related to the increasing multiplicity ofN‐substitution. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Electrochemical, Chemical and Enzymatic Oxidations of Phenothiazines
Authors: Blankert B. , Hayen H. , van Leeuwen S. M. , Karst U. , Bodoki E. , Lotrean S. , Sandulescu R. , Diez N. Mora , Dominguez O. , Arcos J. , Kauffmann J.‐M.
Published: June 2005

The oxidation of several phenothiazine drugs (phenothiazine, promethazine hydrochloride, promazine hydrochloride, trimeprazine hydrochloride and ethopropazine hydrochloride) has been carried out in aqueous acidic media by electrochemical, chemical and enzymatic methods. The chemical oxidation was performed in acetic acid with hydrogen peroxide or in formate buffers using persulfate. The enzymatic oxidation was performed in acetate or ammonium formate buffer by the enzyme horseradish peroxidase in the presence of H2O2. Molecules with, in the lateral chain, two carbon atoms (2C) separating the ring nitrogen and the terminal nitrogen, showed two parallel oxidation pathways, that is (i) formation of the corresponding sulfoxide and (ii) cleavage of the lateral chain with liberation of phenothiazine (PHZ) oxidized products (PHZ sulfoxide and PHZ quinone imine). Molecules with three carbon atoms (3C) separating the two nitrogens were oxidized to the corresponding sulfoxide. The chemical oxidation of all the studied molecules by hydrogen peroxide resulted in the corresponding sulfoxide with no break of the lateral chain. Oxidation by persulfate yielded, for the 3C derivatives, only the corresponding sulfoxide, but it produced cleavage of the lateral chain for the 2C derivatives. The origin of the distinct oxidation pattern between 2C and 3C molecules might be related to steric effects due to the lateral chain. The data are of interest in drug metabolism studies, especially for the early search. In the case of 2C phenothiazines, the results predict the possibility of an in vivo cleavage of the lateral chain with liberation of phenothiazine oxidized products which are known to produce several adverse side effects.
Enzymatic Biosensor Based on Carbon Paste Electrodes Modified with Gold Nanoparticles and Polyphenol Oxidase
Authors: Miscoria Silvia A. , Barrera Gustavo D. , Rivas Gustavo A.
Published: June 2005

The results presented here demonstrate the important catalytic effect of a carbon paste electrode modified by dispersion of gold nanoparticles towards different electroactive compounds. The oxidation of hydrogen peroxide starts at potentials 400 mV less positive than at bare carbon paste, while the reduction, almost negligible at bare carbon paste, starts at 0.100 V. The influence of the size and amount of gold nanoparticles in the composite matrix on the response of the electrode is discussed. The incorporation of albumin within the carbon paste facilitates the dispersion of gold nanoparticles, improving substantially the catalytic effects. At carbon paste modified with gold nanoparticles and albumin, the peak potential separation for hydroquinone decreases from 0.385 V to 0.209 V while the reduction current increases from 16.6 to 75.2 μA. The immobilization of polyphenol oxidase within the carbon paste electrode modified with nanoparticles has allowed us to obtain a very sensitive biosensor for dopamine even in the presence of large excess of ascorbic acid.
Is Voltammetric Current Proportional to the Number of Transferred Electrons for Multi‐Charged Ions or to 3/2 Power of the Number?
Authors: Aoki Koichi
Published: June 2005

Particles with a large number of electrons to transfer, such as nanoparticles and colloidal redox particles, give voltammetrric currents that were demonstrated theoretically to be proportional directly to the number of the electrons, n, rather than to n3/2. The latter quantity is included in the conventional expression for voltammetric peak currents of multi‐charge transfer processes. This apparent contradiction appears depending on whether the charge transfer occurs concurrently (n3/2) or consecutively (n). The expression for the linear sweep voltammetric current was derived from a combination of the diffusion equation for large particles with n electrons and the Nernst equation for the n‐time consecutive one‐electron reactions at the electrode. The power in n for the peak currents, in several voltammetric techniques, was demonstrated to be ascribed to the convolution of the Nernst equation and the diffusion equation.
EQCM Study of Iridium Anodic Oxidation in H2SO4 and KOH Solutions
Authors: Juodkazytė J. , Šebeka B. , Stalnionis G. , Juodkazis K.
Published: June 2005

In the present study anodic oxidation of iridium layer formed thermally on a gold‐sputtered quartz crystal electrode has been investigated by electrochemical quartz crystal microgravimetry (EQCM) in the solutions of 0.5 M H2SO4 and 0.1 M KOH. The emphasis here has been put on the microgravimetric behavior of iridium as a metal, because a few previous EQCM studies reported in literature have been devoted to iridium oxide films (IROFs). The objective pursued here has been to elucidate the nature of the main voltammetric peaks, which occur at different ranges of potential in the solutions investigated. It has been found that anodic oxidation of iridium electrode in 0.5 M H2SO4 and 0.1 M KOH solutions is accompanied by irregular fluctuations of the electrode mass at 0.4 V<E<0.8 V followed by regular increase in mass at 0.8 V<E<1.2 V. The cathodic process initially, at 1.2 V>E>0.9 V, proceeds without any or with slight increase in electrode mass, whereas at E<0.8 V a regular decrease in mass is observed. It has been found that mass to charge ratio characterizing the processes of interest is 2 to 3 g F−1in acidic medium, whereas in the case of alkaline one it is 4 to 6 g F−1. The main pair of peaks seen in the voltammograms of Ir electrode in alkaline medium at E<0.8 V is attributable to redox transition Ir(0)→Ir(III), whereas those observed in the case of acidic medium at E>0.8 V should be related to the redox process Ir(0)→Ir(IV) going via intermediate stage of Ir(III) formation. As a consequence of these redox transitions, the gel‐like surface layer consisting of Ir(III) or Ir(IV) hydrous oxides forms on the electrode surface.
Effect of Albumin on Underpotential Lead Deposition and Stripping on Ag‐RDE
Authors: Hepel Maria
Published: June 2005

The effects of adsorption of bovine serum albumin (BSA) on the electrodeposition and stripping of Pb‐adatoms at a Ag‐RDE in acetate buffer solutions have been studied. The adsorbed BSA molecules have been found to inhibit the lead adsorption process. A decrease in the apparent charge transfer coefficient α for Pb‐adatom desorption from 0.39 to 0.34 in the presence of adsorbed BSA molecules has been attributed to the electric field screening by multiply charged BSA in the adsorption film, since no major lateral interactions between Pb and BSA have been observed. The kinetics of BSA adsorption on a Ag‐RDE was followed by Pb‐adatom probe technique in the range of low BSA coverage, 0<θBSA<0.4. The adsorption (k1) and desorption (k−1) rate constants were determined as follows: k1=2.42×10−4 cm/s, k−1=1.12×10−14 mol cm−2 s−1. The equilibrium constant for BSA adsorption on Ag electrode from 3×10−8 M BSA solution, also determined from the Pb‐adatom probe method, was: Kads=2.17×107 L/mol and the corresponding Gibbs free energy of adsorption: ΔG°ads=−9.99 kcal/mol (−41.85 kJ/mol). The formation of BSA films on Ag electrodes has been confirmed by EQCN mass transients and AFM imaging. It follows from these experiments that BSA molecules adsorb in horizontal orientation and form a film on Ag with 4 nm thickness.
Analysis of Simulated Martian Regolith Using an Array of Ion Selective Electrodes
Authors: Lukow Stefan R. , Kounaves Samuel P.
Published: June 2005

A prototype miniature array of polymer membrane and solid state ion selective electrodes was developed for the purpose of performing an in‐situ analysis of the soluble ionic species in Martian regolith (soil). The array contains a total of 27 electrodes for K+, Na+, Ca2+, Mg2+, NH$\rm{ {_{4}^{+}}}$, Ba2+, NO$\rm{ {_{3}^{-}}}$, Cl−, and Li+, each in triplicate. Barium electrodes were used to indirectly monitor sulfate through precipitation by the addition of barium chloride while the lithium electrodes served as a reference for the array by having a constant lithium concentration as a background for all solutions. The array was tested with several types of simulants, soils, and sawdust from a Mars meteorite, all with varying salt content, meant to approximate the various hypotheses regarding the ionic composition of the Martian soil. The activities of anions and cations determined with the array were compared to ion chromatography data.
Dose–time–response modeling of longitudinal measurements for neurotoxicity risk assessment
Authors: Zhu Yiliang
Published: June 2005

Neurotoxic effects are an important non‐cancer endpoint in health risk assessment and environmental regulation. Neurotoxicity tests such as neurobehavioral screenings using a functional observational battery generate longitudinal dose–response data to profile neurological effects over time. Analyses of longitudinal neurotoxicological data have mostly relied on analysis of variance; explicit dose–time–response modeling has not been reported in the literature. As dose–response modeling has become an increasingly indispensible component in risk assessment as required by the use of benchmark doses, there are strong interests in and needs for appropriate dose–response models, effective model‐fitting techniques, and computation methods for benchmark dose estimation. In this article we propose a family of dose–time–response models, illustrate statistical inference of these models in conjunction with random‐effects to quantify inter‐subject variation, and describe a procedure to profile benchmark dose across time. We illustrate the methods through a dataset from a US/EPA experiment involving the FOB tests on rats administered to a single dose of triethyl tin (TET). The results indicate that the existing functional observational battery data can be utilized for dose–response and benchmark dose analyses and the methods can be applied in general settings of neurotoxicity risk assessment. Copyright © 2005 John Wiley & Sons, Ltd.
Monte Carlo integration strategies for design‐based regression estimators of the spatial mean
Authors: Barabesi L. , Marcheselli M.
Published: June 2005

When a continuous population is sampled, the spatial mean is often the target parameter if the design‐based approach is assumed. In this case, auxiliary information may be suitably used to increase the accuracy of the spatial mean estimators. To this end, regression models are usually considered at the estimation stage in order to implement regression estimators. Since the spatial mean may be obviously represented as a bivariate integral, the strategies for placing the sampling locations are actually Monte Carlo integration methods. Hence, the regression‐based estimation is equivalent to the control‐variate integration method. In this setting, we suggest more refined Monte Carlo integration strategies which may drastically increase the regression estimator accuracy. Copyright © 2005 John Wiley & Sons, Ltd.
Evaluation of optimized variable area transect sampling using totally enumerated field data sets
Authors: Engeman Richard M. , Nielson Ryan M. , Sugihara Robert T.
Published: June 2005

Plotless density estimators (PDEs) can be efficient alternatives to quadrat sampling for estimating the density of stationary objects. Variable area transect (VAT) sampling had been identified, and optimized relative to effort, in previous Monte Carlo simulated population studies as a low‐labor field method that demonstrated superior estimation properties among many PDEs considered. However, natural populations tend to be much more complex and less predictable in spatial distribution than computer generated populations. Therefore, we carried out a Monte Carlo simulation study that used 17 fully enumerated field populations rather than simulated populations. These natural populations represented a variety of population densities and spatial patterns. We focused on assessing the effect of the number of population members searched for along each transect (r), sample size, and transect width on estimation quality. Using relative root mean‐squared error and relative bias as criteria, the optimal range for r was 5 to 7 population members encountered from each start point. Sample size was best if n > 20, but returns in estimation quality diminished by n = 40. Transect width was previously uninvestigated and found to be the most important design factor affecting estimation quality. Field studies should strive for transects as wide as logistically reasonable. Published in 2005 John Wiley & Sons, Ltd.
Testing for separability of space–time covariances
Authors: Mitchell Matthew W. , Genton Marc G. , Gumpertz Marcia L.
Published: June 2005

Separable space–time covariance models are often used for modeling in environmental sciences because of their computational benefits. Unfortunately, there are few formal statistical tests for separability. We adapt a likelihood ratio test based on multivariate repeated measures to the spatio–temporal context. We apply this test to an environmental monitoring data set. Copyright © 2005 John Wiley & Sons, Ltd.
Information content of the fed funds rates
Authors: Sultan Jahangir
Published: June 2005

This study shows that the Fed Funds spot rate mostly affects the level of key interest rates while the Fed Funds futures rate tends to affect both the level and the volatility. Such effects are more concentrated on the shorter segment of the yield curve. In addition, only an unexpected change in the target rate affects both the level and the volatility of interest rates. Finally, the FOMC's increased disclosure of its policy stance has a calming effect on the volatility of key interest rates. © 2005 Wiley Periodicals, Inc. Jrl Fut Mark 25:753–774, 2005
Risk selection in the German public health insurance system
Authors: Nuscheler Robert , Knaus Thomas
Published: June 2005

The German statutory health insurance market was exposed to competition in 1996. To limit direct risk selection the regulator required open enrollment. As the risk compensation scheme, introduced in 1994, is highly incomplete, substantial incentives for risk selection exist. Due to their low premiums, company‐based sickness funds have been able to attract a lot of new members. We analyze, using data from the German Socio‐Economic Panel, the determinants of switching behavior from 1995 to 2000. There is no evidence for selection by funds. The success of the company‐based sickness funds originates in incomplete risk adjustment together with the negative correlation between health status and switching costs. Copyright © 2005 John Wiley & Sons, Ltd.
Pharmaceutical promotion and GP prescription behaviour
Authors: Windmeijer Frank , de Laat Eric , Douven Rudy , Mot Esther
Published: June 2005

The aim of this paper is to empirically analyse the responses by general practitioners to promotional activities for ethical drugs by pharmaceutical companies. Promotion can be beneficial as a means of providing information, but it can also be harmful in the sense that it lowers price sensitivity of doctors and it merely is a means of maintaining market share, even when cheaper, therapeutically equivalent drugs are available. A model is estimated that includes interactions of promotion expenditures and prices and that explicitly exploits the panel structure of the data, allowing for drug specific effects and dynamic adjustments, or habit persistence. The data used are aggregate monthly GP prescriptions per drug together with monthly outlays on drug promotion for the period 1994–1999 for 11 therapeutic markets, covering more than half of the total prescription drug market in the Netherlands. Identification of price effects is aided by the introduction of the Pharmaceutical Prices Act, which established that Dutch drugs prices became a weighted average of the prices in surrounding countries after June 1996. We conclude that GP drug price sensitivity is small, but adversely affected by promotion. Copyright © 2005 John Wiley & Sons, Ltd.
Economic development and the return to human capital: a smooth coefficient semiparametric approach
Authors: Mamuneas Theofanis P. , Savvides Andreas , Stengos Thanasis
Published: June 2005

This paper investigates the impact of human capital on the process of economic growth by allowing the contribution of traditional inputs (capital and labour) as well as that of human capital to vary both across countries and time. The former is accomplished by constructing an index of TFP growth for traditional inputs, while the latter through semiparametric methods. We derive estimates of the output elasticity and social return to human capital for 51 countries at various stages of economic development. Copyright © 2005 John Wiley & Sons, Ltd.
Lymphocytes and the foreign body response: Lymphocyte enhancement of macrophage adhesion and fusion
Authors: Brodbeck William G. , MacEwan Matthew , Colton Erica , Meyerson Howard , Anderson James M.
Published: June 2005

The host foreign body response ensues immediately following implantation of medical devices and prostheses. We have previously identified the role of macrophages in adhering to biomaterial surfaces and guiding the foreign body response while fusing into foreign body giant cells (FBGCs) and concentrating degradative and phagocytic activities. Despite their early and transient presence around implanted biomaterials, few studies have focused on the role of lymphocytes in the foreign body response and biocompatibility. To address this, an in vitro human lymphocyte/macrophage coculture system has been developed. Using this system, it has been shown that when lymphocytes are present during the initial adhesion of monocytes, the rate of monocyte adhesion and fusion is significantly increased (1,500 cells/mm2 and 60%, respectively) when compared to either no lymphocytes present (500 cells/mm2 adhesion and 0% fusion). Although lymphocytes adhered to the tissue culture polystyrene surface, 90% of the lymphocytes were associated with adherent macrophages. However, these cell–cell direct interactions were not necessary to influence macrophage adhesion or fusion as separating the two cell types by a Transwell insert still resulted in significantly increased levels of macrophage adhesion (p < 0.05 when compared to macrophage only cultures). Conversely, the presence of macrophages in Transwell experiments increased lymphocyte proliferation rates at all time points tested. These studies begin to detail the interactions between lymphocytes and macrophages in the absence of known antigen that appropriately relates to the scenarios experienced upon implantation of biomedical devices and the initiation of the foreign body response. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
Ultrastructure of bone healing in defects grafted with a copolymer of polylactic/polyglycolic acids
Authors: Imbronito Ana Vitoria , Scarano Antonio , Orsini Giovanna , Piattelli Adriano , Arana‐Chavez Victor E.
Published: June 2005

Bone substitutes have been used for the treatment of bone defects. The objective of this study was to ultrastructurally evaluate the healing pattern of bone defects filled with a copolymer of polylactic/polyglycolic acid (Fisiograft®) at a time point in which it is expected to be only partially degraded, with the purpose to ultrastructurally analyze how the bone is forming around the grafting material. Three 5‐mm‐diameter bone defects were created in each tibia from 5 rabbits (average weight 2.5 kg) in which the material was randomly implanted. Animals were sacrificed 30 days after surgery and the 30 bone defects were fixed in 2% glutaraldehyde‐2.5% formaldehyde, under microwave irradiation, decalcified in EDTA, embedded in Spurr resin, and examined in a Jeol 1010 TEM. All the bone defects were filled with connective tissue, interspersed with different amounts of the filling material and newly formed bone trabeculae. In areas where the degrading copolymer was present in small amounts, newly formed bone matrix was detected; it was deposited by osteoblast‐like cells in close relation to the copolymer. In areas where the degrading copolymer formed accumulates, an amorphous multilayered material was identified between the connective tissue and the copolymer. In summary, the copolymer of PLA/PGA studied appears to be an osteoconductive material when it is used to fill bone defects. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
Growing up everyone's trusted confidante: Why I really became a psychotherapist
Authors: Kaslow Florence W.
Published: June 2005

This article traces the roots and evolution of my pathway to becoming a psychotherapist and my still evolving professional interests and horizons. It discusses the journey taken, influences felt, and experiences encountered that have contributed to my expanding perspective and modus operandi. It travels from past to present, articulates my current thinking, and describes some of my major involvements in the early 21st century. The words “que sera, sera” (what will be, will be) are also prophetic of the future. © 2005 Wiley Periodicals, Inc. J Clin Psychol/In Session 61: 965–972, 2005.
Becoming and being a psychotherapist: A psychodynamic memoir and meditation
Authors: Orlinsky David E.
Published: June 2005

The author reflects on the circumstances of his becoming a psychotherapist and meditates on their meaning. He notes the effect on his survival through childhood of his grandparents' emigration from Europe and the influence of his close‐knit family on his personal needs and values. He then reflects on his early vocational interests; the transformational power of his education, as a student and faculty, at the University of Chicago; and the constructive force of his professional collaboration and personal friendship with Kenneth Howard. Finally, he considers why it is important to him not only to have become but to continue to be a psychotherapist. © 2005 Wiley Periodicals, Inc. J Clin Psychol/In Session 61: 999–1007, 2005.
Choosing psychotherapy as a career: Why did we cross that road?
Authors: Farber Barry A. , Manevich Inessa , Metzger Jesse , Saypol Erica
Published: June 2005

This article addresses the question “Why do people become psychotherapists?” via two approaches. The first involves an examination of the empirical and clinical literature on motivations and influences common to most psychotherapists. The second approach explores multiple pathways to becoming a psychotherapist by considering distinct gender‐linked career trajectories. We identify 12 oft‐noted themes in the literature on therapists' career paths (e.g., cultural marginalization, a psychologically minded way of understanding self and others) and link these to the narratives of the eight authors in this issue. Finally, we discuss ways in which understanding career motivations may be useful for therapists in their practice. © 2005 Wiley Periodicals, Inc. J Clin Psychol/In Session 61: 1009–1031, 2005.
Choosing psychotherapy as a career: Beyond “I want to help people”
Authors: Norcross John C. , Farber Barry A.
Published: June 2005

This article briefly considers the career determinants of mental health professionals and then introduces the contents of the Journal of Clinical Psychology: In Session issue devoted to “why I became a psychotherapist.” Psychotherapists are assuredly a special sort because the average person prefers to minimize the psychic sufferings of fellow humans and to avoid extensive contact with troubled individuals. Although the most frequent and conscious reason for becoming a psychotherapist is a desire to “help others,” the decision is more complex and multidetermined than that. The multiple, intertwined motives are partly unconscious, impacted by chance encounters, and probably not well understood into late in one's career. © 2005 Wiley Periodicals, Inc. J Clin Psychol/In Session 61: 939–943, 2005.
A database of recombinant viruses and recombinant viral vectors available from the RIKEN DNA bank
Authors: Ugai Hideyo , Murata Takehide , Nagamura Yoshinori , Ugawa Yoshihiro , Suzuki Erika , Nakata Hatsumi , Kujime Yukari , Inamoto Sanae , Hirose Megumi , Inabe Kumiko , Terashima Miho , Yamasaki Takahito , Liu Bingbing , Nakade Koji , Pan Jianzhi , Kimura Makoto , Saito Izumu , Hamada Hirofumi , Obata Yuichi , Yokoyama Kazunari K.
Published: June 2005

Background

Viral vectors are required as gene‐delivery systems for gene therapy and basic research. Recombinant adenoviruses (rAds) expressing genes of interest are being developed as research tools and many studies in vitro and in vivo have already been performed with such rAds.

Methods

Shuttle vectors for rAds were constructed with full‐length cDNAs and rAds were generated in HEK293 cells by the COS‐TPC method. The rAds and shuttle vectors were developed by the Japanese research community and deposited in the RIKEN DNA Bank (RDB; http://www.brc.riken.jp/lab/dna/en/) for distribution to the scientific community. The Recombinant Virus Database (RVD; http://www.brc.riken.jp/lab/dna/rvd/) was established at the RIKEN BioResource Center (BRC) in Japan as the source of information about and distribution of the various resources.

Results

The RIKEN BRC is releasing more than 300 recombinant viruses (RVs) and 500 shuttle vectors, as well as all related information, which is included in a newly established database, the RVD. The RVD consists of (i) information about the RVs, the inserted cDNAs and the shuttle vectors; (ii) data about sequence‐tagged sites (STSs) that are markers of viral DNAs; and (iii) experimental protocols for the use of RVs.

Conclusions

The new database and available resources should be very useful to scientists who are studying human gene therapy and performing related basic research. It is a web‐interfaced flat‐file database that can be accessed through the internet. Moreover, all of the resources deposited in the RDB, which is a public facility in Japan, are available to researchers around the world. Copyright © 2005 John Wiley & Sons, Ltd.
Disjoint directed quadrilaterals in a directed graph
Authors: Zhang Danhong , Wang Hong
Published: June 2005

Let D be a directed graph of order 4k, where k is a positive integer. Suppose that the minimum degree of D is at least 6k − 2. We show that D contains k disjoint directed quadrilaterals with only one exception. © 2005 Wiley Periodicals, Inc. J Graph Theory
Microarrays and expression profiling in microglia research and in inflammatory brain disorders
Authors: Gebicke‐Haerter Peter J.
Published: June 2005

Expression profiling by using microarrays is a powerful tool for investigating transcriptional changes in a variety of diseases. In this survey, microarray data selected from the literature from in vivo and in vitro studies are scrutinized to find differentially expressed genes in common within specific inflammatory conditions in brain or microglial cell cultures, if there are at least two independent investigations available. Viral encephalitis, multiple sclerosis, epileptic seizures, ischemic lesions, and traumatic brain injury are the disorders covered. Moreover, by taking into account expression data obtained from cultured microglia, two examples are presented of how one can deal (or should not deal) with lists of candidate genes showing up in these kinds of studies without sophisticated software programs. Finally, some general remarks are made about pivotal issues when beginning to use microarray technology. © 2005 Wiley‐Liss, Inc.
Visualization of microglia in living tissues using Iba1‐EGFP transgenic mice
Authors: Hirasawa T. , Ohsawa K. , Imai Y. , Ondo Y. , Akazawa C. , Uchino S. , Kohsaka S.
Published: June 2005

Microglia are thought to play important roles not only in repairing injured tissue but in regulating neuronal activity, and visualizing the cells is very useful as a means of further investigating the function of microglia in vivo. We previously cloned the ionized calcium‐binding adaptor molecule 1 (Iba1) gene, which is expressed selectively in microglia/microphages. To generate new transgenic mice to visualize microglia with enhanced green fluorescent protein (EGFP), we here constructed a plasmid carrying EGFP cDNA under control of the Iba1 promoter. This construct was injected into C57B/6 mouse zygotes, and the Iba1‐EGFP transgenic line was developed. Fluorescent in‐situ hybridization analysis revealed that the Iba1‐EGFP transgene was located on chromosome 11D. No obvious defects were observed during development or in adulthood, and the EGFP fluorescence remained invariant over the course of at least four generations. Judging from the immunoreactivity with anti‐Iba1 antibody, all EGFP‐positive cells in the adult brain were ramified microglia. In the developing transgenic embryos, EGFP signals were detected as early as embryonic Day 10.5. The most prominent EGFP signals were found in forebrain, spinal cord, eye, foreleg, yolk sac, liver, and vessel walls. At postnatal Day 6, clear EGFP signals were observed in the supraventricular corpus callosum, known as “fountain of microglia,” where ameboid microglia migrate into the brain parenchyma and mature into ramified microglia. Iba1‐EGFP transgenic mice thus permit observation of living microglia under a fluorescence microscope and provide a useful tool for studying the function of microglia in vivo. © 2005 Wiley‐Liss, Inc.
Norepinephrine protects cortical neurons against microglial‐induced cell death
Authors: Madrigal Jose L.M. , Feinstein Douglas L. , Russo Cinzia Dello
Published: June 2005

Interleukin‐1 beta (IL‐1β) is one of the main cytokines involved in the inflammatory response; it has multiple effects that can contribute to cell damage, one of which is the upregulation of the inducible form of nitric oxide (NO) synthase (NOS2) in certain cell types. We demonstrated previously that in vivo, cortical microglial inflammatory responses were increased when noradrenaline (NE) levels were depleted, suggesting that NE can reduce microglial activation. In the present report, we examined the role of IL‐1β in neurotoxicity induced by microglial‐conditioned media, and possible neuroprotective effects of NE. Incubation of cortical neurons with conditioned media (CM) obtained from lipopolysaccharide (LPS)‐treated microglia induced neuronal NOS2 expression and increased neuronal cell death, and these responses were reduced if the neurons were coincubated with interleukin‐1 receptor antagonist. Cotreatment of microglial cells with LPS plus NE potently blocked IL‐1β production and reduced the ability of the CM to induce neuronal NOS2 and cell death. These results suggest that microglial release of IL‐1β is an important activator of neuronal inflammatory responses, and that protective effects of NE upon neurons involve a reduction of microglial‐derived IL‐1β. © 2005 Wiley‐Liss, Inc.
Microglia and multiple sclerosis
Authors: Jack Carolyn , Ruffini Francesca , Bar‐Or Amit , Antel Jack P.
Published: June 2005

Microglia participate in all phases of the multiple sclerosis (MS) disease process. As members of the innate immune system, these cells have evolved to respond to stranger/danger signals; such a response within the central nervous system (CNS) environment has the potential to induce an acute inflammatory response. Engagement of Toll‐like receptors (TLRs), a major family of pattern‐recognition receptors (PRRs), provides an important mechanism whereby microglia can interact with both exogenous and endogenous ligands within the CNS. Such interactions modulate the capacity of microglia to present antigens to cells of the adaptive immune system and thus contribute to the initiation and propagation of the more sophisticated antigen‐directed responses. This inflammatory response introduces the potential for bidirectional feedback between CNS resident and infiltrating systemic cells. Such interactions acquire particular relevance in the era of therapeutics for MS because the infiltrating cells can be subjected to systemic immunomodulatory therapies known to change their functional properties. Phagocytosis by microglia/macrophages is a hallmark of the MS lesion; however, the extent of tissue damage and the type of cell death will dictate subsequent innate responses. Microglia/macrophages are armed with a battery of effector molecules, such as reactive nitrogen species, that may contribute to CNS tissue injury, specifically to the injury of oligodendrocytes that is associated with MS. A therapeutic challenge is to modulate the dynamic properties of microglia/macrophages so as to limit potentially damaging innate responses, to protect the CNS from injury, and to promote local recovery. © 2005 Wiley‐Liss, Inc.
Neuroprotective role of microglia expressing interleukin‐4
Authors: Park K.W. , Lee D.Y. , Joe E.H. , Kim S.U. , Jin B.K.
Published: June 2005

Little is known about the underlying mechanisms responsible for the death of activated microglia and the functional consequences of the death of these cells, especially in vivo. We show here that intracortical injection of lipopolysaccharide (LPS) led to upregulation of interleukin‐4 (IL‐4) immunoreactivity, followed by a substantial loss of microglia 3 days later, as visualized by complement receptor type 3 (OX‐42) immunostaining and tomato lectin staining. Cells positive for caspase‐3 and terminal deoxynucleotidyl transferase mediated fluorescein‐dUTP nick‐end labeling (TUNEL) were also localized within LPS‐activated microglia. IL‐4 immunoreactivity was detected as early as 12 hr post‐LPS, disappearing at 72 hr. Surprisingly, IL‐4 immunoreactivity was detected exclusively in microglia, but not in astrocytes or neurons. In addition, IL‐4‐neutralizing antibodies markedly increased the survival of activated microglia at 3 days post‐LPS. The expression of inducible nitric oxide synthase (iNOS) and tumor‐necrosis factor (TNF)‐α was sustained in parallel in activated microglia, consequently increasing neuronal cell death. To our knowledge, this study is the first to show the endogenous expression of IL‐4 in LPS‐activated microglia in vivo. Our findings suggest that IL‐4 may regulate brain inflammation by inducing the death of activated microglia in vivo and increasing neuronal survival. © 2005 Wiley‐Liss, Inc.
Perturbations in calcium‐mediated signal transduction in microglia from Alzheimer's disease patients
Authors: McLarnon James G. , Choi Hyun B. , Lue Lih‐Fen , Walker Douglas G. , Kim Seung U.
Published: June 2005

Calcium‐sensitive fluorescence microscopy has been used to study Ca2+‐dependent signal transduction pathways in microglia obtained from Alzheimer's disease (AD) patients and non‐demented (ND) individuals. Data were obtained from nine AD cases and seven ND individuals and included basal levels of intracellular Ca2+ [Ca2+]i, peak amplitudes (Δ[Ca2+]i) and time courses of adenosine triphosphate (ATP) responses and amplitudes of an initial transient response and a subsequent second component of Ca2+ influx through store‐operated channels (SOC) induced by platelet‐activating factor (PAF). Overall, AD microglia were characterized by significantly higher (20%) basal Ca2+ [Ca2+]i relative to ND cells. The Δ[Ca2+]i of ATP and initial phase of PAF responses, which reflect rapid depletion of Ca2+ from endoplasmic reticulum stores, were reduced by respective values of 63% and 59% in AD cells relative to amplitudes recorded from ND microglia. Additionally, AD microglia showed diminished amplitudes (reduction of 61%) of SOC‐mediated Ca2+ entry induced by PAF and prolonged time courses (increase of 60%) of ATP responses with respect to ND microglia. We have generally replicated these results with exposure of human fetal microglia to beta amyloid (5 μM Aβ1–42 applied for 24 hr). Overall, these data indicate significant abnormalities are present in Ca2+‐mediated signal transduction in microglia isolated from AD patients. © 2005 Wiley‐Liss, Inc.