bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, double‐blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: Short‐ and long‐term efficacy and safety results
Authors: Ruperto Nicolino , Nikishina Irina , Pachanov Evgueni D. , Shachbazian Ynessa , Prieur Anne Marie , Mouy Richard , Joos Rik , Zulian Francesco , Schwarz Rudolf , Artamonova Valeria , Emminger Wolfgang , Bandeira Marcia , Buoncompagni Antonella , Foeldvari Ivan , Falcini Fernanda , Baildam Eileen , Kone‐Paut Isabelle , Alessio Maria , Gerloni Valeria , Lenhardt Alessandro , Martini Alberto , Hanft Gertraud , Sigmund Ralf , Simianer Stefan
Published: February 2005

Objective

In an international, multicenter, double‐blind, randomized clinical trial we evaluated the short‐term (3 months) and long‐term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular‐course (oligo‐course) or polyarticular‐course (poly‐course) juvenile idiopathic arthritis (JIA).

Methods

Children ages 2–16 years who had active oligo‐course or poly‐course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double‐blind, double‐dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups.

Results

Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty‐two patients (81%) completed the 12‐month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups.

Conclusion

The short‐ and long‐term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo‐course and poly‐course JIA. The once‐daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.
Cross‐reactivity of human lupus anti‐DNA antibodies with α‐actinin and nephritogenic potential
Authors: Zhao Zeguo , Weinstein Elena , Tuzova Marina , Davidson Anne , Mundel Peter , Marambio Paola , Putterman Chaim
Published: February 2005

Objective

Cross‐reactivity with kidney antigens is believed to be a critical determinant in the renal pathogenicity of anti–double‐stranded DNA (anti‐dsDNA) antibodies. Murine nephritogenic anti‐dsDNA antibodies have been shown to cross‐react with α‐actinin, and anti–α‐actinin antibodies have been found to be deposited in the kidneys of lupus mice with active nephritis. Furthermore, in humans with systemic lupus erythematosus (SLE), it has been found that a greater proportion of polyclonal IgG anti‐dsDNA antibodies from patients with renal involvement bind to α‐actinin than do those from patients without renal disease. We undertook this study to substantiate a direct link between cross‐reactive anti‐dsDNA/anti–α‐actinin antibodies and the pathogenesis of lupus nephritis in humans.

Methods

A panel of 10 anti‐dsDNA and/or anti–α‐actinin antibodies was generated by Epstein‐Barr virus transformation of lymphocytes from patients with SLE and was extensively characterized. Antibody binding was studied by enzyme‐linked immunosorbent assay and Western blotting. Antibody potential for pathogenicity was assessed by measuring binding to isolated glomeruli and mesangial cells and by evaluation of histologic features of the kidney following injection in vivo.

Results

All anti‐dsDNA antibodies isolated also bound α‐actinin. Cross‐reactive antibodies bound to mesangial cells and to isolated glomeruli ex vivo. Binding to glomeruli was not inhibited by DNase treatment, but could be abrogated by α‐actinin. Furthermore, histopathologic abnormalities seen in mice injected intraperitoneally with a cross‐reactive cell line included fusion of podocyte foot processes and subepithelial and subendothelial deposition.

Conclusion

These studies provide strong support for the hypothesis that α‐actinin is a major cross‐reactive target for anti‐dsDNA antibodies in SLE patients. Cross‐reactive anti‐dsDNA/anti–α‐actinin antibodies from SLE patients are pathogenic and may contribute to the kidney lesions in lupus nephritis.
Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor
Authors: Mueller Ruediger B. , Skapenko Alla , Grunke Mathias , Wendler Jörg , Stuhlmuller Bruno , Kalden Joachim R. , Schulze‐Koops Hendrik
Published: February 2005

Objective

Tumor necrosis factor (TNF)–neutralizing agents are the most successful means of ameliorating systemic autoimmune inflammation. Neutralization of TNF, however, is often associated with the development of autoantibodies, particularly to nuclear antigens, and the mechanisms of this are unknown. We undertook this study to analyze the effect of TNF and its neutralization on the expression of major histocompatibility complex class II molecules and on the function of antigen‐presenting myeloid cells in rheumatoid arthritis (RA).

Methods

Monocytes were isolated from the peripheral blood of RA patients before and after anti‐TNF monoclonal antibody (mAb) treatment and from the peripheral blood of controls by negative selection, differentiated in vitro to macrophages, and analyzed by flow cytometry for HLA–DR expression. T cell responses to activation by myeloid cells were assessed in proliferation assays, and messenger RNA (mRNA) levels of the class II transactivator (CIITA) were determined by semiquantitative reverse transcriptase–polymerase chain reaction.

Results

HLA–DR expression was significantly reduced on myeloid cells from RA patients with active disease, but was increased to normal levels after anti‐TNF mAb treatment. Concordantly, in vitro application of TNF to monocytes from healthy individuals reduced their ability to up‐regulate HLA–DR during differentiation to macrophages and, importantly, inhibited their ability to stimulate T cells in mixed lymphocyte reactions. Molecular analysis revealed that the effect of TNF on HLA–DR expression was mediated via suppression of the transcription factor CIITA.

Conclusion

The data indicate that TNF decreases HLA–DR expression by reducing CIITA mRNA levels in myeloid cells, functionally resulting in a decreased capacity of myeloid cells to stimulate T cells. Concordantly, ameliorating disease activity in chronic inflammatory diseases by neutralizing TNF restores expression of HLA–DR on myeloid cells as well as the ability of myeloid cells to stimulate T cells. Thus, anti‐TNF treatment might lead to augmented T cell activation by myeloid cells, thereby promoting immune responses to (auto)antigens and the development of antinuclear antibodies that are frequently associated with anti‐TNF therapy.
A near‐contact binary: CN Andromedae
Authors: Çiçek C. , Erdem A. , Soydugan F.
Published: February 2005

New BVR light curves and photometric analysis of the eclipsing binary star CN And are presented. The shape of the light curves are typical of β Lyr type, and there are large asymmetries between maxima. The BVR light curves and the radial velocity curves (from Rucinski et al. 2000) were solved with the Wilson‐Devinney method, simultaneously. The results suggest that CN And is a almost contact binary system, in which the component stars are filling ∼99% of their Roche lobes. We discuss the model with a large dark starspot on the more massive star and a bright substellar spot on the companion to account for the light curve asymmetries. The absolute parameters of the system were also derived. The system resembles the near contact binary V1010 Oph according to its Roche configuration and light curve asymmetries. We, also, discuss the evolution of the system: it seems to be in a transition phase to the contact era. All previous times of minimum light were collected and combined with the new ones presented in this work. The variation of the orbital period of the system was then analyzed. The results reveal that the orbital period has a secular decrease of about 1.98 ± 0.04 sec per century, which corresponds to a conservative mass transfer from the more to the less massive component at a rate of (1.52 ± 0.09) × 10–7 m⊙/yr or a mass loss from the primary component due to magnetic stellar winds at a rate of (7.83 ± 0.09) × 10–8 m⊙/yr. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
A “lost” sunspot observation in 1785
Authors: Vaquero J. M. , Trigo R. M. , Gallego M. C.
Published: February 2005

The reconstruction of the solar activity during some years of the 18th century is poorly known because there are scarce sunspot observations. The aim of this short contribution is to present a “lost” sunspot observation realized by the Portuguese scientist Sanches Dorta during his observation of the solar eclipse of 1785 from Rio de Janeiro (Brazil). This record was not included in the database compiled by Hoyt and Schatten (1998). We present new estimations of the solar activity during 1785. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
A new look at the position of the 1604 Supernova (V843 Ophiuchi)
Authors: Green D. W. E.
Published: February 2005

The position of the supernova of 1604 (V843 Oph) is re‐assessed, with relevant discussion pertaining to the present‐day remnant, 3C 358. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Few projections astrotomography: radio astronomical approach to 3D reconstruction
Authors: Agafonov M. I. , Sharova O. I.
Published: February 2005

We develop a radio astronomical approach to 3D‐reconstruction in few projections tomography. It is based on the 2‐CLEAN DSA method which consists of two clean algorithms by using a synthesized beam. In complex cases two extreme solutions are used for the analysis of the image structure. These solutions determine the limits of permissible energy redistribution on the image among the components of small and large scales. Two variants of 3D‐reconstruction proceeding from a set of two‐dimensional projections (3D2D) and from a set of one‐dimensional ones (3D1D) are considered. It is shown that the quality of 3D2D‐reconstruction should be similar to the quality of 2D1D‐reconstruction if the same number of equally spaced scans is used. But a doubled number of projections is required for 3D1D‐reconstruction. We have simulated 3D‐reconstruction of an optically thin emitting object. The present technique is a component of astrotomography and it has good prospects for a wide range of remote sensing. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Pulsational properties of V2109 Cyg
Authors: Özel N. , Kirbiyik H. , Civelek R. , Kiziloğlu N.
Published: February 2005

In this study V2109 Cyg (a pulsating δ Scuti star) has been modelled. In treating the oscillation equations perturbation in gravitational potential energy has been taken into account. Both radial and nonradial oscillations are treated with adiabatic approximation. The so called radial fundamental frequency (5.3745 c/d) and the nonradial frequency (5.8332 c/d) were obtained within a satisfactory precision. It was found that the Cowling approximation introduced more error as one went from low overtones to high overtones in radial oscillations. A similar trend was observed in nonradial case with low values of l. By keeping the effective temperatures almost the same as with V2109 Cyg two more models with different masses have also been calculated to see the effect of inclusion of perturbation in gravitational potential energy on oscillation frequencies in different masses. Conclusion arrived is that one must be careful to employ the Cowling approximation especially for high nonradial oscillation frequencies. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Light‐time effect in the eclipsing binary system AM Leonis
Authors: Albayrak B. , Selam S. O. , Ak T. , Elmasli A. , Özavci İ.
Published: February 2005

We report four new times of minimum light and the improved ephemeris for the well known contact binary AM Leo. The O‐C diagram, constructed with all reliable timings found in the literature was analyzed and the the light‐time effect in the system was confirmed. We found a periodicity of 44.82 years in the O‐C residuals with an amplitude of 0.0058 day. The periodic curve representing the O‐C values is asymmetric indicating a large eccentricity of 0.73 of the third body orbit. The mass of the third body is found to be 0.175 M⊙ for the orbital inclination of the eclipsing pair's orbit. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Working in collaboration—a therapeutic intervention for abused children
Authors: Barker Richard , Place Maurice
Published: February 2005

In this article we report and reflect upon a service offered in one locality of the UK to children who have been abused. The evaluation shows the value of close working relationships between agencies, and the very positive way that such interventions are viewed by the children and those involved with their care. It is also evident that an eclectic style of therapeutic work is able to produce improvement in aspects of the children's behaviour, most particularly in the area of family life and relationships. Copyright © 2005 John Wiley & Sons, Ltd.
Clinical supervision in child protection for community nurses
Authors: Lister Pam Green , Crisp Beth R.
Published: February 2005

Community nurses have been recognized as having a key role in the protection and care of children, particularly in relation to the identification and detection of child abuse. In order to fulfill this role in a competent manner, they need to have access to appropriate supervision. The aim of this paper is to explore community nurses' and health care managers' understanding and experience of clinical supervision in child protection. The findings presented here were collected as part of a larger study commissioned by the Greater Glasgow Primary Health Care National Health Service (NHS) Trust. Ninety‐nine nurses and nursing managers were interviewed, either individually or in groups, about their professional involvement in child protection issues and support for their involvement in child protection work, as well as their current knowledge and perceived training needs. The interview data was subjected to a thematic analysis. A lack of consensus was found among nurses and managers in Glasgow as to what constitutes clinical supervision and a good deal of variation in nurses' experiences of clinical supervision in the field of child protection. The historical difficulties with regard to supervision were attributed to several aspects of nursing culture. However, both nurses and managers emphasized the need for formal, regular, systematic supervision for all nurses regardless of their specific role with regard to child protection. Copyright © 2005 John Wiley & Sons, Ltd.
Commercial and sexual exploitation of children and young people in the UK—a review
Authors: Chase Elaine , Statham June
Published: February 2005

This paper reviews recent information and data relevant to the commercial sexual exploitation of children and young people in the UK. Three main aspects of exploitation are addressed: abuse through prostitution; abuse through pornography; and the trafficking of children and young people to and through the UK for the purposes of commercial sexual exploitation. Most published research in this area relates to young people exploited through prostitution. The review explores the range of vulnerability factors, the processes used to engage young people in prostitution and the types of support strategies for those being exploited. Rather less information is currently available on the scale of child pornography, or the links between the use of pornography and other forms of sexual abuse. The internet as a modern technology for proliferating child pornography is discussed, alongside its role in providing opportunities for paedophiles to access and ‘groom’ children for sexual purposes. Finally, the review provides a summary of research on trafficking of children to and through the UK for the purposes of commercial sexual exploitation and demonstrates the limited knowledge about this topic. Copyright © 2005 John Wiley & Sons, Ltd.
Thermal‐ and Photoinduced Spin‐State Switching in an Unprecedented Three‐Dimensional Bimetallic Coordination Polymer
Authors: Niel Virginie , Thompson Amber L. , Goeta Andrés E. , Enachescu Cristian , Hauser Andreas , Galet Ana , Muñoz M. Carmen , Real José A.
Published: February 2005

The compound {Fe(pmd)[Ag(CN)2][Ag2(CN)3]} (pmd=pyrimidine) was synthesized and characterized. Magnetic, calorimetric and single crystal visible spectroscopic studies demonstrate the occurrence of a two‐step high‐spin (HS) ⇄ low‐spin (LS) transition. The critical temperatures areTc1=185 andTc2=148 K. Each step involves ∼50 % of the iron centers, with the low‐temperature step showing a hysteresis of 2.5 K. The enthalpy and entropy variations associated with the two steps are ΔH1=3.6±0.4 kJ mol−1and ΔS1=19.5±3 J K−1 mol−1; ΔH2=4.8±0.4 kJ mol−1and ΔS2=33.5±3 J K−1 mol−1. Photomagnetic and visible spectroscopy experiments show that below 50 K, where the LS state is the thermodynamically stable state, the compound can be switched quantitatively to the HS state using green‐red light (550–650 nm). HS‐to‐LS relaxation experiments in the dark at temperatures between 15 and 55 K show that the relaxation takes place via a two‐step cooperative process, which was analyzed in the context of the mean field theory. The crystal structure has been studied at 290, 220, 170, 90 and 30 K together with 30 K after irradiation. The compound adopts monoclinic symmetry (P21/c,Z=16) at all temperatures. There are five [FeN6] pseudo‐octahedral sites linked by pmd, [Ag(CN)2]−and [Ag2(CN)3]−bridging ligands to form an unprecedented three‐dimensional (6,6) topology. The structural analysis allows for an understanding of the microscopic mechanism of the two‐step behavior of the thermally induced spin transition as well as the corresponding relaxation of the photoexcited compound based on the individual changes of the five sites. Synergy between metallophilic interactions and the spin transition is also shown by the variation of the Ag⋅⋅⋅Ag distances. Correlations between the variation of the unit‐cell volume and the change of Ag⋅⋅⋅Ag interactions within each step with the asymmetric change of the anomalous heat capacity have also been inferred.
Heterogene Kondensation – Ein Konditionierverfahren zur Abscheidung submikroner Partikeln aus Gasströmen
Authors: Heidenreich S.
Published: February 2005

Durch heterogene Kondensation von Wasserdampf lassen sich submikrone Partikeln so konditionieren, dass sie mit geringem Aufwand aus Gasströmen abgeschieden werden können. Das Prinzip, das dahinter steht, ist einfach: Durch Kondensation lagert sich Flüssigkeit an die feinen Partikeln an, die Masse und damit die Trägheit der Teilchen nimmt zu, und die Abscheidung der so vergrößerten Teilchen wird deutlich vereinfacht. Es gelingt, feinste Partikeln mit Größen bis hinab in den Nanometerbereich mit speziellen Tropfenabscheidern oder einfachen Trägheitsabscheidern abzuscheiden. Nach einer Darstellung der grundlegenden Vorgänge der heterogenen Kondensation – Erzeugung einer übersättigten Dampfphase, Tropfenbildung und Tropfenwachstum – wird ein Überblick über die verschiedenen Möglichkeiten zur Konditionierung und Abscheidung feinster Partikeln mittels heterogener Kondensation gegeben.
Nanofasern und Nanoröhrchen: Bausteine aus Polymeren
Authors: Dersch Roland , Greiner Andreas , Steinhart Martin , Wendorff Joachim H.
Published: February 2005

Als Querschnittstechnologie befruchtet die Nanotechnologie ein breites Spektrum von Anwendungsfeldern, das sich von der Optoelektronik über die Umwelttechnik, die Chemietechnik, die Sensorik, die Biotechnologie bis zur Medizin und Pharmazie hinzieht. Nanoröhrchen und Nanofasern stellen in diesen Bereichen eine vielseitige Plattform dar. Zu ihrer Herstellung und weiteren Funktionalisierung wurden eine Reihe von speziellen Verfahren wie das Elektrospinnen und das Templatverfahren auf der Basis von Nanofasern und mesoporösen Materialien entwickelt. Sie erlauben die Präparation der Nanoobjekte aus Polymeren, Metallen, Keramiken, Gläsern und Materialkombinationen. Die Integration solcher Objekte in größere Bauteile ist die nächste Herausforderung.
Metallnanopartikel als Einelektronenschalter: Nanotechnologie: Schlüsseltechnologie des neuen Jahrhunderts?
Authors: Schmid Günter
Published: February 2005

Die Nanotechnologie lässt die klassischen Unterschiede zwischen Physik, Chemie und Biologie verschwinden. Sie ist auf dem Weg zur dominierenden Technologie des neuen Jahrhunderts und wird den Alltag der Menschen maßgebend beeinflussen. Am Beispiel von Metallnanopartikeln werden Möglichkeiten für die Herstellung neuartiger Computergenerationen erläutert, die dem Silicium‐Zeitalter folgen könnten.
Von der Höhlenmalerei zur Schlüsseltechnologie: Nanoanwendung: enormes wirtschaftliches Potenzial
Authors: Ottersbach Peter , Schmitz Christiane , Averdung Johannes , Heinrich Lothar , Gutsch Andreas
Published: February 2005

Nanomaterialien und ultradünne Beschichtungen von Nanopartikeln werden die Eigenschaften vieler künftiger Produkte bestimmen: Ultraharte Oberflächen, superschnelle Computer, schmutzabweisende Oberflächen, neuartige Krebsbehandlungsmethoden, kratzfeste Beschichtungen, preiswerte Solarzellen, preiswerte Displays und druckbare Elektronik. Der Markt für Nanotechnologieprodukte wächst zweistellig und wird im Jahr 2010 mehrere hundert Millarden US‐Dollar betragen.
Isolierende Nanoschäume
Authors: Schädler Volker , du Fresne von Hohenesche Cedric
Published: February 2005

Seit gut eineinhalb Jahren arbeiten Wissenschaftler der BASF am Straßburger Institut de Science et d´Ingénierie Supramoléculaires (ISIS) an materialwissenschaftlichen Fragestellungen. Das internationale Team sucht u.a. neue Wege zur Herstellung von nanoporösen Polymerschäumen – diese Materialien könnten in Zukunft aufgrund ihrer deutlich geringeren Wärmeleitfähigkeit klassische Schaumstoff‐Wärmeisolatoren ersetzen.
Nanokapseln für Substanzen mit großer Wirkung
Authors: Borchard‐Tuch Claudia
Published: February 2005

Bereits Mitte der Sechzigerjahre hatte man die Idee einer medizinischen Anwendung der Nanotechnologie: In dem Film “Fantastische Reise” wird eine Gruppe mutiger Ärzte in einem U‐Boot so stark verkleinert, dass sie durch die Adern eines Patienten fahren und ein lebensbedrohliches Blutgerinnsel aus seinem Gehirn entfernen kann. In den letzten 35 Jahren gab es große Fortschritte bei der Herstellung hoch komplizierter Strukturen, welche sogar noch kleiner sind. Zu ihnen gehören die Nanokapseln. Sie eröffnen die Möglichkeit, Wirkstoffe in nanometergroßen Behältern unterzubringen, aus denen sie gezielt freigesetzt werden.
Results of a phase I study utilizing monocyte‐derived dendritic cells pulsed with tumor RNA in children with stage 4 neuroblastoma
Authors: Caruso Denise A. , Orme Lisa M. , Amor Gerlinda M. , Neale Alana M. , Radcliff Fiona J. , Downie Peter , Tang Mimi L. K. , Ashley David M.
Published: February 2005

BACKGROUND

A Phase I study of 11 pediatric patients with newly diagnosed, Stage 4 neuroblastoma was conducted using monocyte‐derived dendritic cells (DC) pulsed with tumor RNA to produce antitumor vaccines (DCRNA).

METHODS

Patients received two courses of induction with carboplatin followed by standard chemotherapy, surgery, radiation, high‐dose therapy, stem cell rescue, and DCRNA vaccine therapy.

RESULTS

The results showed that this method for producing and administering DCRNA from a single leukapheresis product was both feasible and safe in this pediatric neuroblastoma population. Two courses of carboplatin maintained lymphocyte counts at normal levels. However, immune function 6 weeks after high‐dose chemotherapy and stem cell rescue and prior to receiving DCRNA was impaired in all patients tested. There was an alteration in the ratio of CD4‐positive and CD80‐positive T cells. CD4‐positive cell numbers were below normal, whereas CD8‐positive cell numbers were above normal for all patients. In addition, CD19‐positive cell numbers were below normal for all but one patient. It was found that humoral responses to recall antigens (diphtheria and tetanus) and cellular responses to mitogen and recall antigens were below normal in most patients. Despite this, two of three patients tested showed a tumor‐specific humoral immune response to DCRNA. Among the patients who had measurable disease at the time of DCRNA vaccine, none showed any objective tumor response.

CONCLUSIONS

DCRNA vaccines were both safe and feasible in children with Stage 4 neuroblastoma. Humoral responses to tumor were detected, although remained immunosuppressed at the time of administration, limiting efficacy. Cancer 2005. © 2005 American Cancer Society.
Impact of radiographic findings on prognosis for skin carcinoma with clinical perineural invasion
Authors: Galloway Thomas J. , Morris Christopher G. , Mancuso Anthony A. , Amdur Robert J. , Mendenhall William M.
Published: February 2005

BACKGROUND

The objective of the current study was to correlate pretreatment computed tomography and magnetic resonance imaging studies with outcomes for patients with squamous or basal cell carcinoma of the skin and clinical perineural invasion.

METHODS

Between 1986 and 2002, 45 patients were treated with radiotherapy alone (21 patients) or combined with surgery (24 patients), and 4 patients received concomitant chemotherapy. Follow‐up ranged from 0.85 years to 17.4 years (median, 3.8 years). Patients were stratified as follows: imaging negative, 10 patients; minimal or moderate peripheral disease, 14 patients; and central and/or macroscopic disease, 21 patients.

RESULTS

The 5‐year local control rates were as follows: imaging negative, 76%; minimal or moderate peripheral disease, 57%; and central and/or macroscopic disease, 25%. The 5‐year absolute and cause‐specific survival rates were as follows: imaging negative, 90% and 100%, respectively; minimal or moderate peripheral disease, 50% and 56%, respectively; and central and/or macroscopic disease, 58% and 61%, respectively.

CONCLUSIONS

Patients who had symptomatic but imaging‐negative perineural invasion had a relatively good prognosis after receiving definitive radiotherapy alone or combined with surgery. Patients who had imaging‐positive minimal or moderate peripheral disease had a better local control rate but a similar survival rate compared with patients who had central and/or macroscopic disease. Cancer 2005. © 2005 American Cancer Society.
Influence of diabetic metabolic state on fracture healing in spontaneously diabetic rats
Authors: Follak Niels , Klöting Ingrid , Merk Harry
Published: February 2005

Background

Type 1 diabetes mellitus (DM) has been shown to alter the properties of bone and impair fracture healing in both humans and animals. The objective of this study was to examine changes in the histomorphometrical, histological and mechanical parameters of bone and remodeling during fracture healing, depending on the diabetic metabolic state in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats, a rat strain that represents a close homology to DM in man.

Methods

On the basis of blood glucose values at the time of surgery, postoperative blood glucose course and postoperative insulin requirements, 90 spontaneously diabetic BB/OK rats were divided into groups with well‐compensated or poorly compensated metabolic state. Forty‐five LEW.1A rats served as the normoglycemic controls. The femurs were fractured in a standardized procedure and then allowed to heal for 2, 4 and 6 weeks.

Results

Our study showed that, in terms of bone histomorphometry, within the first 4 weeks after fracture, severe mineralization disorders occurred exclusively in the rats with poorly compensated diabetic metabolic states with a significant decrease of all fluorochrome‐based parameters of mineralization, apposition, formation and timing of mineralization, as well as a delay in cellular differentiation and significantly decreased values of biomechanical properties in comparison to the spontaneously diabetic rats with well‐compensated metabolic states and to the control rats.

Conclusions

With a controlled insulin therapy and a resulting well‐compensated diabetic metabolic state, mineralization and cellular differentiation disorders, as well as the decreased values of biomechanical properties in the fracture repair in the poorly compensated diabetic metabolic state with very severe hyperglycemia can be avoided. Copyright © 2005 John Wiley & Sons, Ltd.
QALYs and the capability approach
Authors: Cookson Richard
Published: February 2005

This explores the applicability of Sen's capability approach to the economic evaluation of health care programmes. An individual's ‘capability set’ describes his freedom to choose valuable activities and states of being (‘functionings’). Direct estimation and valuation of capability sets is not feasible at present. Standard preference‐based methods such as willingness to pay are feasible, but problematic due to the adaptive and constructed nature of individual preferences over time and under uncertainty. An alternative is to re‐interpret the QALY as a cardinal and interpersonally comparable index of the value of the individual's capability set. This approach has limitations, since the link between QALYs and capabilities is not straightforward. Nevertheless, the QALY approach is recognisable as an application of the capability approach since it pays close attention to functionings, through the use of survey‐based multi‐attribute health state valuation instruments, and permits conceptions of value other than the traditional utilitarian ones of choice, desire‐fulfilment and happiness. Furthermore, suitably re‐interpreted, it can account for (i) non‐separability between health and non‐health components of value; and suitably modified it can also account for (ii) process attributes of care, which may have a direct effect on non‐health functionings such as comfort and dignity, and (iii) sub‐group diversity in the value of the same health functionings. Copyright © 2005 John Wiley & Sons, Ltd.
Monitoring structural change in dynamic econometric models
Authors: Zeileis Achim , Leisch Friedrich , Kleiber Christian , Hornik Kurt
Published: February 2005

The classical approach to testing for structural change employs retrospective tests using a historical data set of a given length. Here we consider a wide array of fluctuation‐type tests in a monitoring situation—given a history period for which a regression relationship is known to be stable, we test whether incoming data are consistent with the previously established relationship. Procedures based on estimates of the regression coefficients are extended in three directions: we introduce (a) procedures based on OLS residuals, (b) rescaled statistics and (c) alternative asymptotic boundaries. Compared to the existing tests our extensions offer ease of computation, improved size in finite samples for dynamic models and better power against certain alternatives, respectively. We apply our methods to three data sets, German M1 money demand, US labour productivity and S&P 500 stock returns. Copyright © 2005 John Wiley & Sons, Ltd.
An algorithm to reduce the occupational space in gender segregation studies
Authors: Herranz Neus , Mora Ricardo , Ruiz‐Castillo Javier
Published: February 2005

This paper presents an algorithm based on the bootstrap to select an admissible aggregation level, that is, the minimum number of occupational categories that yield a gender segregation value not significantly smaller than that obtained from the large number of occupational categories usually available in any data set. The approach is illustrated using labour force survey data for Spain for the comparison of gender segregation in 1977 and 1992, as well as 1994 and 2000. To measure gender segregation, an additively decomposable segregation index based on the entropy concept is used. Despite a substantial simplification in the size of the occupation space, the decrease in the segregation index is very small and not significant, regardless of the year. Consequently, intertemporal changes in gender segregation can be studied using a greatly reduced classification of occupations that permits an easier interpretation of results. Copyright © 2005 John Wiley & Sons, Ltd.
Physical characteristics of small intestinal submucosa scaffolds are location‐dependent
Authors: Raghavan Devanathan , Kropp Bradley P. , Lin H‐K. , Zhang Yuanyuan , Cowan Richard , Madihally Sundararajan V.
Published: February 2005

Using biodegradable scaffolds as an alternative to engineer new tissues has become an attractive candidate in various transplantation protocols. In particular, small intestinal submucosa (SIS), a dense connective matrix harvested from the small intestine, has gained attention due to a number of favorable properties. However, use of SIS is constrained by obtaining reliable, reproducible products in large‐scale preparations that affect the regenerative process. To better understand the heterogeneous nature of SIS, this study focused on evaluating the location‐dependent alterations in the physical characteristics of the matrices harvested from distal and proximal ends and processed in‐house (referred as hand‐made). Additionally, results were compared with a commercially available machine‐made Cook® SIS. Tensile properties during monotonic loading and cyclical loading were compared in wet conditions. Furthermore, permeability of these membranes to urea was analyzed using a custom‐built chamber, and the microarchitecture was analyzed via scanning electron microscopy. These results showed that distal samples were more elastic and less permeable to urea relative to other samples. However, permeability in each sample was direction‐dependent, that is, mucosal to serosal direction was less permeable compared to sorasal to mucosal direction in all the samples. Cook® SIS was more susceptible to cyclical loading and had a shorter range of load carrying capacity. In summary, results show that physical characteristics of SIS are location‐dependent. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res 73A: 90–96, 2005
Improved greedy algorithm for protein structure reconstruction
Authors: Tuffery Pierre , Guyon Frédéric , Derreumaux Philippe
Published: February 2005

This article concerns the development of an improved greedy algorithm for protein structure reconstruction. Our stochastic greedy algorithm, which attempts to locate the ground state of an approximate energy function, exploits the fact that protein structures consist of overlapping structural building blocks that are not independent. Application of this approach to a series of 16 proteins with 50–250 amino acids leads to predicted models deviating from the experimental structures by 0.5 Å RMSD using an RMSD‐based energy function and within 1.5 to 4.8 Å RMSD using a Go‐based energy function. The Go‐based results are significant because they illustrate the strength of combining structural fragments and stochastic greedy algorithms in capturing the native structures of proteins stabilized by long‐range interactions separated by more than 30 amino acids. These results clearly open the door to less computationally demanding solutions to predict structures from sequences. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 506–513, 2005
SARS‐CoV protease inhibitors design using virtual screening method from natural products libraries
Authors: Liu Bing , Zhou Jiaju
Published: February 2005

Two natural products databases, the marine natural products database (MNPD) and the traditional Chinese medicines database (TCMD), were used to find novel structures of potent SARS‐CoV protease inhibitors through virtual screening. Before the procedure, the databases were filtered by Lipinski's ROF and Xu's extension rules. The results were analyzed by statistic methods to eliminate the bias in target‐based database screening toward higher molecular weight compounds for enhancing the hit rate. Eighteen lead compounds were recommended by the screening procedure. They were useful for experimental scientists in prioritizing drug candidates and studying the interaction mechanism. The binding mechanism was also analyzed between the best screening compound and the SARS protein. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 484–490, 2005
Transferability of parameters of strictly local geminals' wave function and possibility of sequential derivation of molecular mechanics
Authors: Tokmachev A. M. , Tchougréeff A. L.
Published: February 2005

The problem of substantiation of molecular mechanics (MM) remains actual due to growing popularity of hybrid quantum/classical (QM/MM) schemes. Recently proposed deductive molecular mechanics (DMM) seems to be a natural tool to derive mechanistic models of molecular energy (classical force fields) from a suitable quantum mechanical (QM) description of molecular structure. It is based on an assumption that the trial wave function underlying the MM description is one of the antisymmetrized product of strictly local geminals (SLG). A proof of transferability of electronic structure parameters (ESPs) in this approximation is an essential component of a logical framework for the transition from the QM to an MM description because it allows constructing expressions for potential energy surfaces by proper consideration of the response of the ESPs to the variations of geometry parameters. In the present article the ESPs defining density matrix elements and basis one‐electron states (hybrid orbitals—HOs) in the SLG approximation are formally considered. The transferability of the density matrix elements with respect to the parameters of molecular electronic structure and the linear response relations for the HOs are proven to take place under very nonrestrictive conditions. Special attention is paid to numerical estimates of the ESPs' features giving an “experimental” support to approximate expressions for the molecular energy. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 491–505, 2005
Genetic approaches for the induction of a CD4+ T cell response in cancer immunotherapy
Authors: Bonehill Aude , Heirman Carlo , Thielemans Kris
Published: February 2005

Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long‐lasting anti‐tumor immune response. CD4+ T helper cells, and in particular IFN‐γ‐secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer‐specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti‐cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide‐binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development. Copyright © 2005 John Wiley & Sons, Ltd.
Femoral intra‐arterial injection: a tool to deliver and assess recombinant AAV constructs in rodents whole hind limb
Authors: Gonin Patrick , Arandel Ludovic , Van Wittenberghe Laetitia , Marais Thibaut , Perez Norma , Danos Olivier
Published: February 2005

With the aim of simplifying recombinant‐adeno‐associated virus (rAAV) delivery in muscle, a new femoral intra‐arterial technique was designed and tested in rodents (rats and mice). Two serotypes, several promoters and transgenes (reporter or therapeutic) were tested using this administration route. The new route is both easy to perform and efficient. Its usefulness as a tool to assess gene delivery constructs in the muscle was established in the context of recombinant AAV serotypes 1 and 2, and with the ubiquitous CMV and two muscle‐specific (C5‐12 and CK6) promoters. Both serum monitoring of a secreted protein (murine alkaline phosphatase: muSEAP) and slide staining were used to compare the different constructs. Significantly different patterns of expression in kinetics of expression (muSEAP) and homogeneity of fiber transduction (staining) were evidenced with the different promoters tested, and compared with intra‐muscular expression patterns. Detailed studies of differential transduction in leg and thigh muscles showed equivalent efficacy, except in rectus femoris, and to a lesser extent in soleus. In light of these results and prior data, intra‐arterially mediated gene transfer mechanism is discussed. Copyright © 2005 John Wiley & Sons, Ltd.
No evidence for germ‐line transmission following prenatal and early postnatal AAV‐mediated gene delivery
Authors: Jakob Marcus , Mühle Christiane , Park Jung , Weiß Susi , Waddington Simon , Schneider Holm
Published: February 2005

Background

Recombinant adeno‐associated viruses have been used successfully in a number of pre‐clinical and clinical gene therapy studies. Since there is a broad consensus that gene therapy must not lead to germ‐line transmission, the potential of such vectors for inadvertent gene transfer into germ cells deserves special attention. This applies in particular to pre‐ or perinatal vector application which has been considered for diseases presenting with morbidity already at birth.

Methods

AAV serotype 2 derived vectors carrying a β‐galactosidase reporter gene or human clotting factor IX cDNA were injected intraperitoneally or via a yolk sac vein into mouse fetuses or administered intravascularly to newborn mice. Tissue samples of the treated animals including the gonads as well as sperm DNA, obtained by differential lysis of one testis of each male animal, and the offspring of all treated mice were investigated for the presence of vector DNA by nested PCR. In positive samples, the copy number of the vector was determined by quantitative real‐time PCR.

Results

AAV vectors administered intraperitoneally or intravascularly to fetal or newborn mice reached the gonads of these animals and persisted there for time periods greater than one year. Intravascular injection of the vector resulted more frequently in gene transfer to the gonads than intraperitoneal injection. Vector copy numbers in the gonads ranged from 0.3 to 74 per 104 cell equivalents. However, neither in isolated sperm DNA from the treated animals nor in their offspring were vector sequences detectable.

Conclusions

These data suggest the risk of inadvertent germ‐line transmission following prenatal or early postnatal AAV type 2 mediated gene delivery to be very low. Copyright © 2005 John Wiley & Sons, Ltd.
Enhancement of gene delivery to human airway epithelial cells in vitro using a peptide from the polyoma virus protein VP1
Authors: Wiseman John W. , Scott Emily S. , Shaw Paul A. , Colledge William H.
Published: February 2005

Background

Current liposome‐based gene delivery methods for therapeutic benefit are limited by their low efficiency. One possible way to improve gene expression is to include a peptide with a nuclear localization signal (NLS) to enhance the movement of the transfection complex from the cytoplasm to the nuclei of target cells. We have tested a synthetic peptide based on the amino terminal region of the polyoma virus VP1 protein. This region has non‐overlapping motifs for DNA binding and nuclear localization.

Methods

Luciferase gene transfer efficiency was evaluated using this peptide and a control peptide with a mutated NLS in subconfluent, confluent and polarized human bronchial epithelial (16HBE) cells compared to lipoplex alone.

Results

Gene transfer efficiency with a lipopolyplex containing the VP1 peptide enhanced gene delivery compared to lipoplex. Transfection with a lipopolyplex containing the control peptide failed to enhance gene delivery. The VP1 peptide increased the amount of plasmid associated with the nucleus while the mutant VP1 peptide did not. The order of lipopolyplex formation was important, with greatest enhancement when peptide was added to the plasmid before addition of the liposome. A bipartite peptide with the VP1 sequence and an integrin‐binding motif (RGD) resulted in a reduction in gene transfer efficiency compared to lipoplex. Cell adhesion studies showed that the integrin binding associated with the RGD motif was lost when it was attached to the VP1 sequence. The combination of the two peptide sequences in cis may have compromised the function of both.

Conclusions

Our results indicate that the VP1 peptide represents a strategy to enhance liposome‐mediated gene delivery to airway epithelia in vitro. Comparison of transfection efficiencies between the VP1 and the mutant VP1 peptides and the direct measurement of plasmid associated with the nucleus suggests that this enhancement is caused by the NLS signal sequence in the peptide. Copyright © 2005 John Wiley & Sons, Ltd.
Comparative studies of the capsid precursor polypeptide P1 and the capsid protein VP1 cDNA vectors for DNA vaccination against foot‐and‐mouth disease virus
Authors: Yang Ning‐Sun , Wang Jeng‐Hwan , Lin Ku‐Feng , Wang Chien‐Yu , Kim Suk‐Am , Yang Yu‐Ling , Jong Ming‐Hwa , Kuo Tsun‐Yung , Lai Shiow‐Suey , Holland Cheng R. , Chan Ming‐Tsair , Liang Shu‐Mei
Published: February 2005

Background

Foot‐and‐mouth disease virus (FMDV) causes a severe livestock disease, and the virus is an interesting target for virology and vaccine studies.

Materials and methods

Here we evaluated comparatively three different viral antigen‐encoding DNA sequences, delivered via two physical means (i.e., gene gun delivery into skin and electroporation delivery into muscle), for naked DNA‐mediated vaccination in a mouse system.

Results

Both methods gave similar results, demonstrating commonality of the observed DNA vaccine effects. Immunization with a cDNA vector expressing the major viral antigen (VP1) alone routinely failed to induce the production of anti‐VP1 or neutralizing antibodies in test mice. As a second approach, the plasmid L‐VP1 that produces a transgenic membrane‐anchored VP1 protein elicited a strong antibody response, but all test mice failed in the FMDV challenge experiment. In contrast, for mice immunized with the viral capsid precursor protein (P1) cDNA expression vector, both neutralizing antibodies and 80–100% protection in test mice were detected.

Conclusions

This strategy of using the whole capsid precursor protein P1 cDNA for vaccination, intentionally without the use of virus‐specific protease or other encoding genes for safety reasons, may thus be employed as a relevant experimental system for induction or upgrading of effective neutralizing antibody response, and as a convenient surrogate test system for DNA vaccination studies of FMDV and presumably other viral diseases. Copyright © 2005 John Wiley & Sons, Ltd.